Substituted α, β-anellated butyrolactones

ABSTRACT

The present invention relates to novel substituted (α,β-fused butyrolactones, to processes for their preparation and to their use for the prevention and/or treatment of disorders caused by hyper- or hypofunction of the glutamatergic system, in particular of cerebral ischaemias, craniocerebral trauma, states of pain or CNS-mediated spasms.

The present invention relates to α,β-fused butyrolactones, to processes for their preparation and to their use as pharmaceuticals.

The amino acid L-glutamate is the most important excitatory neurotransmitter in the brain. Glutamate receptors can be divided into two major classes: 1. ionotropic receptors which control ion channels directly and 2. metabotropic receptors (mGluRs).

Metabotropic glutamate receptors are a heterogeneous class of G-protein-coupled receptors. Pre- and postsynaptically, they modulate the release of glutamate and the sensitivity of the cell to glutamate, respectively. The effects are caused via different second-messenger cascades. This response, in turn, has an effect on the ionotropic glutamate receptors.

Presently, 8 different subtypes of metabotropic glutamate receptors are known, differing in the second-messenger cascade, pharmacology and the localization in the brain (review in: Ann. Rev. Pharmacol. Toxicol. 1997, 37, 205) .

The present invention relates to α,β-fused butyrolactones of the general formula (I)

in which

A represents radicals of the formulae —CH₂—, —CO—, —CR⁴(OH)— or —(CH₂)_(a)—CHR⁵—,

 in which

a represents a number 0, 1, 2, 3 or 4,

R⁴ represents hydrogen or (C₁-C₆)-alkyl

and

R⁵ represents phenyl,

 or

 represents (C₂-C₈)-alkanediyl, (C₂-C₆)-alkenediyl or (C₂-C₆)-alkinediyl,

R¹ represents hydrogen, (C₃-C₆)-cycloalkyl or represents a 5- to 6-membered heterocycle which may contain up to 3 heteroatoms from the group consisting of S, O, N and/or a radical of the formula —NR⁶,

 in which

R⁶ represents hydrogen or methyl,

or

 represents a 5- to 6-membered benzo-fused heterocycle which may contain up to 2 heteroatoms from the group consisting of S, O, N and/or a radical of the formula —NR⁷, and which may be attached both via the phenyl ring and via the heterocycle,

 in which

R⁷ has the meaning of R⁶ given above and is identical to or different from this meaning,

or

 represents radicals of the formulae

 in which

b and c are identical or different and represent a number 1 or 2,

or

 represents (C₆-C₁₀)-aryl,

 where all of the ring systems listed above are optionally mono- to polysubstituted by identical or different substituents selected from the group consisting of halogen, cyano, nitro, trifluoromethyl, hydroxyl, (C₁-C₆)-alkoxy, (C₁-C₆)-alkyl-carbonyloxy and (C₃-C₆)-cycloalkyl, phenyl, phenoxy, benzyloxy and a 5- to 6-membered aromatic heterocycle having up to 3 heteroatoms from the group consisting of S, N and/or O, which for their part may be substituted up to three times by identical or different substituents from the group consisting of cyano and halogen,

 and/or are substituted by (C₁-C₆)-alkyl and (C₂-C₆)-alkylene, which for their part may be substituted by halogen, (C₆-C₁₀)-aryl or by radicals of the formula —SR⁸, —OR⁹ or —NR¹⁰R¹¹ or

 in which

R⁸ represents (C₁-C₆)-alkyl or phenyl,

R⁹ represents hydrogen or (C₁-C₆)-alkyl,

and

R¹⁰ and R¹¹ are identical or different and represent hydrogen, phenyl or (C₁-C₆)-alkyl, which is optionally substituted by phenyl, which for its part may be mono- to polysubstituted by identical or different substituents from the group consisting of halogen, nitro, hydroxyl and (C₁-C₆)-alkoxy,

or

R¹⁰ and R¹¹ together with the nitrogen atom form a radical of the formula

 in which

G represents an oxygen atom, a —CH₂— group or a radical of the formula —NR¹²—,

 in which

R¹² represents hydrogen, phenyl, benzyl, (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy-carbonyl or a 5- to 6-membered aromatic heterocycle having up to 3 heteroatoms from the group consisting of S, N and/or O,

 and/or are substituted by groups of the formulae —CO₂—R¹³, —NR¹⁴R¹⁵, —NR¹⁶CO—R¹⁷, —NR¹⁸CO₂—R¹⁹ and —CO—NR²⁰R²¹,

 in which

R¹³ represents hydrogen, or represents (C₁-C₉)-alkyl or (C₂-C₆)-alkenyl, which for their part may be substituted by radicals of the formulae

 (C₆-C₁₀)-aryl or by a 5- to 7-membered aromatic heterocycle having up to 3 heteroatoms from the group consisting of S, N and/or O,

 in which

d represents a number 1 or 2,

or

 represents (C₆-C₁₀)-aryl, which is optionally substituted by phenyl, which for its part may be substituted by cyano or halogen,

R¹⁴ and R¹⁵ are identical or different and represent hydrogen, (C₃-C₆)-cycloalkyl, phenyl or (C₁-C₆)-alkyl, which is optionally substituted by (C₃-C₆)-cycloalkyl or phenyl, which for its part may be mono- to polysubstituted by identical or different substituents from the group consisting of halogen, hydroxyl or (C₁-C₆)-alkoxy,

R¹⁶ represents hydrogen or (C₁-C₆)-alkyl,

R¹⁷ represents hydrogen, adamantyl, (C₃-C₈)-cycloalkyl, (C₂-C₆)-alkenyl or (C₁-C₁₂)-alkyl which is optionally substituted by adamantyl, (C₃-C₆)-cycloalkyl, (C₆-C₁₀)-aryl, phenoxy or a 5- to 6-membered aromatic heterocycle having up to 4 heteroatoms from the group consisting of S, N and/or O, where aryl and the heterocycle for their part may be mono- to polysubstituted by identical or different substituents from the group consisting of (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy, hydroxyl, nitro or halogen,

 and/or alkyl is optionally substituted by a radical of the formula

 in which

e represents a number 0 or 1 and

R²² represents (C₁-C₆)-alkyl or (C₆-C₁₀)-aryl, which is optionally mono- to polysubstituted by identical or different substituents from the group consisting of halogen, nitro, hydroxyl and (C₁-C₆)-alkoxy,

or

 represents (C₆-C₁₀)-aryl or a 5- to 6-membered aromatic heterocycle having up to 3 heteroatoms from the group consisting of S, N and/or O, which for their part may optionally be mono- to polysubstituted by identical or different substituents from the group consisting of (C₁-C₆)-alkoxy, (C₁-C₆)-alkyl, hydroxyl, nitro and halogen,

or

 represents a radical of the formula

 in which

L and M are identical or different and represent hydrogen or halogen,

R²³ and R²⁴ have the meaning of R¹⁰ and R¹¹ given above and are identical to or different from this meaning,

R ¹⁸ has the meaning of R¹⁶ given above and is identical to or different from this meaning,

R¹⁹ represents (C₃-C₈)-cycloalkyl, or represents (C₁-C₈)-alkyl or (C₂-C₈)-alkenyl, which for their part are optionally substituted by substituents selected from the group consisting of halogen, phenyl, hydroxyl, morpholinyl, (C₃-C₈)-cycloalkyl and by a group of the formula —SiR²⁵R²⁶R²⁷,

 in which

R²⁵, R²⁶ and R²⁷ are identical or different and represent (C₁-C₆)-alkyl,

R²⁰ and R²¹ are identical or different and represent hydrogen, adamantyl, (C₃-C₈)-cycloalkyl, phenyl, phenoxy-substituted phenyl or a 5- to 6-membered, aromatic heterocycle having up to 3 heteroatoms from the group consisting of S, N and/or O, or

 represent (C₂-C₈)-alkenyl, (C₁-C₁₂)-alkyl or (C₂-C₆)-alkinyl, which are optionally substituted by hydroxyl, (C₃-C₆)-cycloalkyl, (C₁-C₆)-alkoxy, halogen, hydroxyl, trifluoromethyl, phenyl or by a 5- to 6-membered aromatic heterocycle having up to 3 heteroatoms from the group consisting of S, N and/or O, where the ring systems are optionally substiutted up to 2 times by identical or different substituents from the group consisting of (C₁-C₆)-alkoxy, (C₁-C₆)-alkoxycarbonyl, halogen, phenoxy, hydroxyl and (C₁-C₆)-alkyl,

 and/or the alkyl listed under R²⁰/R²¹ is optionally substituted by radicals of the formulae

 in which

R²⁸ and R²⁹ are identical or different and represent hydrogen or (C₁-C₆)-alkyl,

or

 represents a radical of the formula

 in which

R³⁰ has the meaning of R¹² given above and is identical to or different from this meaning,

or

R²⁰ and R²¹ together with the nitrogen atom form a radical of the formula

 in which

G′ has the meaning of G given above and is identical to or different from this meaning,

R² and R³ are identical or different and represent hydrogen or (C₁-C₆)-alkyl,

and

D and E together form radicals of the formulae

 in which

R³¹, R³², R³³, R³⁴, R³⁵, R³⁶, R³⁷ and R³⁸ are identical or different and represent hydrogen, phenyl or (C₁-C₆)-alkyl,

and their pharmaceutically acceptable salts.

The compounds according to the invention can exist in stereoisomeric forms which either behave as image and mirror image (enantiomers), or which do not behave as image and mirror image (diastereomers). The invention relates both to the enantiomers or diastereomers and their respective mixtures. Like the diastereomers, the racemic forms can be separated into the stereoisomerically uniform components in a known manner.

Physiologically acceptable salts of the compounds according to the invention can be salts of the substances according to the invention with mineral acids, carboxylic acids or sulphonic acids. Particular preference is given, for example, to salts with hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, ethanesulphonic acid, toluenesulphonic acid, benzenesulphonic acid, naphthalenedisulphonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid or benzoic acid.

Salts which can be mentioned are salts with customary bases, such as, for example, alkali metal salts (for example sodium or potassium salts), alkaline earth metal salts (for example calcium or magnesium salts) or ammonium salts, derived from ammonia or organic amines, such as, for example, diethylamine, triethylamine, ethyldiisopropylamine-amine, procaine, dibenzylamine, N-methylmorpholine, dihydroabietylamine, 1-ephen-amine or methylpiperidine.

In the context of the invention, (C₃-C₈)-cycloalkyl and (C₃-C₆)-cycloalkyl represent cyclopropyl, cyclopentyl, cyclobutyl, cyclohexyl, cycloheptyl or cyclooctyl. Preferred examples which may be mentioned are: cyclopropyl, cyclopentyl, cyclohexyl or cycloheptyl.

In general, (C₆-C₁₀) represents an aromatic radical having 6 to 10 carbon atoms. Preferred aryl radicals are phenyl and naphthyl.

In the context of the invention, (C₁-C₁₂)-alkyl, (C₁-C₉)-alkyl, (C₁-C₈)-alkyl and (C₁-C₆)-alkyl represent a straight-chain or branched alkyl radical having 1 to 12, 1 to 9, 1 to 8 and 1 to 6 carbon atoms, respectively. Preference is given to a straight-chain or branched alkyl radical having 1 to 6 carbon atoms. Examples which may be mentioned are: methyl, ethyl, n-propyl, isopropyl, t-butyl, n-pentyl and n-hexyl.

In the content of the invention, (C₂-C₈)-alkanediyl represents a straight-chain or branched alkanediyl radical having 2 to 8 carbon atoms. Preference is given to a straight-chain or branched alkanediyl radical having 2 to 6 carbon atoms, particularly preferably 2 to 4 carbon atoms. Examples which may be mentioned are ethylene, propylene, propane-1,2-diyl, propane-2,2-diyl, butane-1,3-diyl, butane-2,4-diyl, pentane-2,4-diyl, 2-methyl-pentane-2,4-diyl.

In the content of the invention, (C₂ -C₆)-alkenediyl represents a straight-chain or branched alkenediyl radical having 2 to 6 carbon atoms, preferably 2 to 4 carbon atoms, particularly preferably 3 carbon atoms. Examples which may be mentioned are ethene-1,2-diyl, ethene-1,1-diyl, propene-1,1-diyl, propene-1,2-diyl, propene-1,3-diyl, propene-3,3-diyl, propene-2,3-diyl, but-2-ene-1,4-diyl, pent-2-ene-1,4-diyl, hex-2-ene-1,4-diyl.

In the context of the invention, (C₂-C₆)-alkinediyl represents a straight-chain or branched alkinediyl radical having 2 to 6 carbon atoms, preferably 2 to 4 carbon atoms, particularly preferably 2 to 3 carbon atoms. Examples which may be mentioned are ethine-1,2-diyl, propine-1,3-diyl, but-2-ine-1,4-diyl, pent-2-ine-1,4-diyl, hex-2-ine-1,4-diyl.

In the context of the invention, (C₁-C₆)-alkoxy represents a straight-chain or branched alkoxy radical having 1 to 6 carbon atoms. Preference is given to a straight-chain or branched alkoxy radical having 1 to 4 carbon atoms. Examples which may be mentioned are: methoxy, ethoxy, n-propoxy, isopropoxy, t-butoxy, n-pentoxy and n-hexoxy.

In the context of the invention, (C₁-C₆)-alkoxycarbonyl represents a straight-chain or branched alkoxycarbonyl radical having 1 to 6 carbon atoms. Preference is given to a straight-chain or branched alkoxycarbonyl radical having 1 to 4 carbon atoms. Examples which may be mentioned are: methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl and t-butoxycarbonyl.

In the context of the invention, (C₂-C₈)-alkenyl and (C₂-C₆)-alkenyl represent a straight-chain or branched alkenyl radical having 2 to 8 carbon atoms and 2 to 6 carbon atoms, respectively. Preference is given to a straight-chain or branched alkenyl radical having 2 to 4 carbon atoms. Examples which may be mentioned are: vinyl, allyl, isopropenyl and n-but-2-en-1-yl.

In the context of the invention, (C₂-C₆)-alkinyl represents a straight-chain or branched alkinyl radical having 2 to 6 carbon atoms. Preference is given to a straight-chain or branched alkinyl radical having 2 to 4 carbon atoms. Examples which may be mentioned are: ethinyl, n-prop-2-in-1-yl and n-but-2-in-1-yl.

In the context of the invention, a 5- to 6-membered heterocycle generally represents a 5- to 6-membered, optionally also aromatic, heterocycle which may contain up to 3 heteroatoms from the group consisting of S, O and/or N or a radical of the formula —NH or —NCH₃. Examples which may be mentioned are: pyridyl, pyrimidyl, pyridazinyl, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, piperidinyl or morpholinyl. Preference is given to pyridyl, pyrimidyl, pyridazinyl, furyl and thiazolyl.

In the context of the invention, a 5- to 6-membered, benzo-fused heterocycle generally represents a 5- to 6-membered, preferably 5-membered heterocycle having up to 2 heteroatoms from the group consisting of S, O, N and/or a radical of the formula —NH, whose ring carbon atoms are the attachment points for the benzene ring. Examples which may be mentioned are: indolyl, benzimidazole, benzothiophenyl, benzofuranyl, benzoxazolyl, quinolyl, quinoxalinyl or quinazolyl. Preference is given to benzimidazole, quinolyl, quinoxalinyl, quinazolyl, benzothiophenyl and benzofuranyl.

Preference is given to compounds of the general formula (I) according to the invention,

in which

A represents radicals of the formulae —CH₂—, —CO—, —CR⁴(OH)— or —(CH₂)_(a)—CHR⁵—,

 in which

a represents a number 0, 1, 2 or 3,

R⁴ represents hydrogen or (C₁-C₄)-alkyl

and

R⁵ represents phenyl,

or

 represents (C₂-C₆)-alkanediyl, (C₂-C₄)-alkenediyl or (C₂-C₄)-alkinediyl,

R¹ represents hydrogen, cyclopropyl, cyclopentyl or cyclohexyl, or represents benzofuranyl, benzothiophenyl, benzimidazolyl, thienyl, furyl, quinazolyl, quinoxalinyl or quinolyl,

or

 represents radicals of the formulae

 in which

b and c are identical or different and represent a number 1 or 2,

or

 represents phenyl or naphthyl,

 where all of the ring systems listed above are optionally mono- to polysubstituted by identical or different substituents selected from the group consisting of fluorine, chlorine, bromine, iodine, cyano, nitro, trifluoromethyl, hydroxyl or (C₁-C₅)-alkoxy, (C₁-C₅)-alkyl-carbonyloxy, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, phenoxy, pyridyl, pyrimidyl, pyridazinyl, thienyl, furyl or benzyloxy, which for their part may be substituted up to three times by identical or different substituents from the group consisting of cyano, fluorine, chlorine, bromine and iodine,

 and/or are substituted by (C₁-C₅)-alkyl and (C₂-C₄)-alkenyl, which for their part may be substituted by fluorine, chlorine, bromine, iodine, phenyl, naphthyl or by radicals of the formula —SR⁸, —OR⁹ or —NR¹⁰R¹¹ or

 in which

R⁸ represents (C₁-C₄)-alkyl or phenyl,

R⁹ represents hydrogen or (C₁-C₄)-alkyl,

and

R¹⁰ and R¹¹ are identical or different and represent hydrogen, phenyl or (C₁-C₄)-alkyl, which is optionally substituted by phenyl, which for its part may be mono- to polysubstituted by identical or different substituents from the group consisting of fluorine, chlorine, bromine, nitro, hydroxyl and (C₁-C₄)-alkoxy,

or

R¹⁰ and R¹¹ together with the nitrogen atom form a radical of the formula

 in which

G represents an oxygen atom, a —CH₂— group or a radical of the formula —NR¹²—,

 in which

R¹² represents hydrogen, phenyl, benzyl, (C₁-C₄)-alkyl, (C₁-C₄)-alkoxycarbonyl, pyridyl, pyrimidyl, pyridazinyl or furyl,

 and/or are substituted by groups of the formulae —CO₂—R¹³, —NR¹⁴R¹⁵, —NR¹⁶CO—R¹⁷, —NR¹⁸CO₂—R¹⁹ and —CO—NR²⁰R²¹,

 in which

R¹³ represents hydrogen, or represents (C₁-C₈)-alkyl or (C₂-C₅)-alkenyl, which for their part may be substituted by radicals of the formulae

 phenyl, naphthyl, pyridyl, thienyl or furyl,

 in which

d represents a number 1 or 2,

or

 represents phenyl or naphthyl, which are optionally substituted by phenyl, which for its part may be substituted by cyano, fluorine, chorine or bromine,

R¹⁴ and R¹⁵ are identical or different and represent hydrogen, cyclopropyl, cyclopentyl, cyclohexyl, phenyl or (C₁-C₅)-alkyl, which is optionally substituted by cyclopropyl, cyclopentyl, cyclohexyl or phenyl, which for its part may be mono- to polysubstituted by identical or different substituents from the group consisting of fluorine, chlorine, bromine, hydroxyl or (C₁-C₄)-alkoxy,

R¹⁶ represents hydrogen or (C₁-C₃)-alkyl,

R¹⁷ represents hydrogen, adamantyl, cyclopropyl, cyclopentyl or cyclohexyl, or represents (C₂-C₄)-alkenyl or (C₁-C₁₀)-alkyl, which is optionally substituted by adamantyl, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, phenoxy-naphthyl, pyridyl, thienyl, tetrazolyl or furyl, where the ring systems for their part may be mono- to polysubstituted by identical or different substituents from the group consisting of (C₁-C₄)-alkyl, (C₁-C₄)-alkoxy, hydroxyl, nitro, fluorine, chlorine and bromine,

 and/or alkyl is optionally substituted by a radical of the formula

 in which

e represents a number 0 or 1 and

R²² represents (C₁-C₄)-alkyl, phenyl or naphthyl, which are optionally mono- to polysubstituted by identical or different substituents from the group consisting of fluorine, chlorine, bromine, nitro, hydroxyl and (C₁-C₄)-alkoxy,

or

 represents phenyl, naphthyl, thienyl, furyl or pyridyl, which for their part may optionally be mono- to polysubstituted by identical or different substituents from the group consisting of (C₁-C₄)-alkoxy, (C₁-C₄)-alkyl, hydroxyl, nitro, fluorine, chlorine and bromine,

or

 represents a radical of the formula

 in which

L and M are identical or different and represent hydrogen, fluorine, chlorine or bromine,

R²³ and R²⁴ have the meaning of R¹⁰ and R¹¹ given above and are identical to or different from this meaning,

R¹⁸ has the meaning of R¹⁶ given above and is identical to or different from this meaning,

R¹⁹ represents cyclopropyl, cyclopentyl or cyclohexyl, or represents (C₁-C₇)-alkyl or (C₂-C₆)-alkenyl, which for their part are optionally substituted by substituents selected from the group consisting of fluorine, chlorine, bromine, phenyl, hydroxyl, morpholinyl, cyclopropyl, cyclopentyl, cyclohexyl and by a group of the formula —SiR²⁵R²⁶R²⁷,

 in which

R²⁵, R²⁶ and R²⁷ are identical or different and represent (C₁-C₄)-alkyl,

R²⁰ and R²¹ are identical or different and represent hydrogen, adamantyl, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, phenoxy-substituted phenyl, pyridyl, furyl, thienyl, thiazolyl or pyrryl, or

 represent (C₂-C₆)-alkenyl, (C₁-C₁₀)-alkyl or (C₃-C₆)-alkinyl, which are optionally substituted by hydroxyl, cyclopropyl, cyclopentyl, cyclohexyl, (C₁-C₅)-alkoxy, (C₁-C₆)-alkoxycarbonyl, fluorine, chlorine, bromine, hydroxyl, trifluoromethyl, phenyl, pyridyl, furyl, thienyl or pyrryl, where the ring systems are optionally substituted up to 2 times by identical or different substituents from the group consisting of (C₁-C₄)-alkoxy, fluorine, chlorine, bromine, phenoxy, hydroxyl or (C₁-C₄)-alkyl,

 and/or the alkyl listed under R²⁰/R²¹ is optionally substituted by radicals of the formulae

—SCF₃

 or —NR²⁸R²⁹,

 in which

R²⁸ and R²⁹ are identical or different and represent hydrogen or (C₁-C₄)-alkyl,

or

 represents a radical of the formula

 in which

R³⁰ has the meaning of R¹² given above and is identical to or different from this meaning,

or

R²⁰ and R²¹ together with the nitrogen atom form a radical of the formula

 in which

G′ has the meaning of G given above and is identical to or different from this meaning,

R² and R³ are identical or different and represent hydrogen or (C₁-C₃)-alkyl,

and

D and E together form radicals of the formulae

 in which

R³¹, R³², R³³, R³⁴, R³⁵, R³⁶, R³⁷ and R³⁸ are identical or different and represent hydrogen, phenyl or (C₁-C₃)-alkyl,

and their pharmaceutically acceptable salts.

Particular preference is given to compounds of the general formula (I) according to the invention,

in which

A represents radicals of the formulae —CH₂—, —CO—, —CR⁴(OH)— or —(CH₂)_(a)—CHR⁵—,

 in which

a represents a number 0, 1, 2 or 3,

R⁴ represents hydrogen or (C₁-C₃)-alkyl

and

R⁵ represents phenyl,

or

 represents (C₂-C₄)-alkanediyl, propenediyl or (C₂-C₃)-alkinediyl,

R¹ represents hydrogen, cyclopropyl or cyclohexyl, or represents benzofuranyl, benzothiophenyl, benzimidazolyl, thienyl, quinazolyl or quinoxalinyl,

or

 represents radicals of the formulae

 in which

b and c are identical or different and represent a number 1 or 2,

or

 represents phenyl or naphthyl,

 where all of the ring systems listed above are optionally mono- to polysubstituted by identical or different substituents selected from the group consisting of fluorine, chlorine, bromine, iodine, cyano, nitro, trifluoromethyl or (C₁-C₄)-alkoxy, (C₁-C₄)-alkyl-carbonyloxy, cyclohexyl, phenyl, phenoxy, pyridyl, pyrimidyl, pyridazinyl or benzyloxy, which for their part may be substituted up to three times by identical or different substituents from the group consisting of cyano, fluorine, chlorine, bromine and iodine,

 and/or are substituted by (C₁-C₄)-alkyl and (C₂-C₃)-alkenyl, which for their part may be substituted by chlorine, bromine, iodine or phenyl or by radicals of the formula —OR⁹ or —NR¹⁰R¹¹ or

 in which

R⁹ represents hydrogen or (C₁-C₃)-alkyl,

and

R¹⁰ and R¹¹ are identical or different and represent hydrogen, phenyl or (C₁-C₃)-alkyl, which is optionally substituted by phenyl, which for its part may be substituted by chlorine, bromine, hydroxyl or (C₁-C₃)-alkoxy,

or

R¹⁰ and R¹¹ together with the nitrogen atom form a radical of the formula

 in which

G represents an oxygen atom or a radical of the formula —NR¹²,

 in which

R¹² represents hydrogen, phenyl, benzyl, (C₁-C₃)-alkyl, (C₁-C₃)-alkoxycarbonyl, pyridyl, pyrimidyl, pyridazinyl or furyl,

 and/or are substituted by groups of the formulae —CO₂—R¹³, —NR¹⁴R¹⁵, —NR¹⁶CO—R¹⁷, —NR¹⁸CO₂—R¹⁹ and —CO—NR²⁰R²¹,

 in which

R¹³ represents hydrogen, or represents (C₁-C₆)-alkyl or allyl, which for their part may be substituted by radicals of the formulae

 phenyl, naphthyl or pyridyl,

 in which

d represents a number 1 or 2,

or

 represents phenyl, which is optionally substituted by phenyl, which for its part may be substituted by cyano, chlorine or bromine,

R¹⁴ and R¹⁵ are identical or different and represent hydrogen, cyclohexyl, phenyl or (C₁-C₄)-alkyl, which is optionally substituted by cyclopropyl, cyclohexyl or phenyl, which for its part may be mono- to polysubstituted by identical or different substituents from the group consisting of chlorine and (C₁-C₃)-alkoxy,

R¹⁶ represents hydrogen, methyl or ethyl,

R¹⁷ represents hydrogen, adamantyl, cyclopentyl or cyclohexyl, or represents (C₂-C₃)-alkenyl or (C₁-C₈)-alkyl, which is optionally substituted by adamantyl, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, phenoxy, thienyl or furyl, where the ring systems for their part may be mono- to polysubstituted by identical or different substituents from the group consisting of (C₁-C₃)-alkyl, (C₁-C₃)-alkoxy, hydroxyl, nitro, fluorine, chlorine and bromine,

 and/or alkyl is optionally substituted by a radical of the formula

 in which

e is a number 0 or 1 and

R²² represents (C₁-C₃)-alkyl, phenyl or naphthyl, which are optionally mono- to polysubstituted by identical or different substituents from the group consisting of fluorine, chlorine, bromine, nitro, hydroxyl and (C₁-C₃)-alkoxy,

or

 represents phenyl, naphthyl, thienyl or furyl, which for their part may optionally be mono- to polysubstituted by identical or different substituents from the group consisting of (C₁-C₃)-alkoxy, (C₁-C₃)-alkyl, nitro, fluorine, chlorine and bromine,

or

 represents a radical of the formula

 or —NR²³R²⁴,

 in which

L and M are identical or different and represent hydrogen, fluorine or chlorine,

R²³ and R²⁴ have the meaning of R¹⁰ and R¹¹ given above and are identical to or different from this meaning,

R¹⁸ has the meaning of R¹⁶ given above and is identical to or different from this meaning,

R¹⁹ represents (C₁-C₄)-alkyl or (C₃-C₅)-alkenyl, which for their part are optionally substituted by substituents selected from the group consisting of chlorine, phenyl, hydroxyl, morpholinyl, cyclopropyl, cyclohexyl and by a group of the formula —SiR²⁵R²⁶R²⁷,

 in which

R²⁵, R²⁶ and R²⁷ are identical and represent methyl,

R²⁰ and R²¹ are identical or different and represent hydrogen, adamantyl, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, phenoxy-substituted phenyl, thiazolyl or pyrryl, or represent (C₂-C₃)-alkenyl, (C₁-C₇)-alkyl or (C₃-C₅)-alkinyl, which are optionally substituted by hydroxyl, cyclopropyl, cyclopentyl, cyclohexyl, (C₁-C₃)-alkoxy, hydroxyl, trifluoromethyl, phenyl, pyridyl, furyl, thienyl or pyrryl, where the ring systems are optionally substituted up to 2 times by identical or different substituents from the group consisting of (C₁-C₃)-alkoxy, (C₁-C₆)-alkoxycarbonyl, fluorine, chlorine, bromine, phenoxy, hydroxyl and (C₁-C₃)-alkyl,

 and/or the alkyl listed under R²⁰/R²¹ is optionally substituted by radicals of the formulae

—SCF₃,

 or —NR²⁸R²⁹,

 in which

R²⁸ and R²⁹ are identical or different and represent hydrogen or (C₁-C₃)-alkyl,

or

R²⁰ or R²¹ represents a radical of the formula

 in which

R³⁰ has the meaning of R¹² given above and is identical to or different from this meaning,

or

R²⁰ and R²¹ together with the nitrogen atom form a radical of the formula

 in which

G′ has the meaning of G given above and is identical to or different from this meaning,

R² and R³ are identical or different and represent hydrogen or methyl,

and

D and E together form radicals of the formulae

 in which

R³¹, R³², R³³, R³⁴, R³⁵, R³⁶, R³⁷ and R³⁸ are identical or different and represent hydrogen or methyl,

and their pharmaceutically acceptable salts.

Particular preference is likewise given to compounds of the general formula (I) according to the invention in which A represents the —CH₂— group.

Very particular preference is given to compounds of the general formula (I) according to the invention, in which

A represents —CH₂—,

R¹ represents phenyl or naphthyl,

 where all of the abovementioned ring systems are optionally mono- to polysubstituted by identical or different substituents selected from the group consisting of fluorine, chlorine, bromine, iodine, cyano, nitro, trifluoromethyl or (C₁-C₄)-alkoxy,

 and/or are substituted by (C₁-C₄)-alkyl,

 and/or are substituted by groups of the formulae —NR¹⁶CO—R¹⁷, —NR¹⁸CO₂—R¹⁹ and —CO—NR²⁰R²¹,

 in which

R¹⁶ is hydrogen,

R¹⁷ is (C₁-C₈)-alkyl, which is optionally substituted by cyclopropyl, cyclopentyl, cyclohexyl, phenyl, thienyl or furyl, where the ring systems for their part may be mono- to polysubstituted by identical or different substituents from the group consisting of (C₁-C₃)-alkyl, (C₁-C₃)-alkoxy, hydroxyl, nitro, fluorine, chlorine and bromine,

R¹⁸ has the meaning of R given above and is identical to or different from this meaning,

R¹⁹ represents (C₁-C₄)-alkyl or (C₃-C₅)-alkenyl,

R²⁰ and R²¹ are identical or different and represent hydrogen, (C₂-C₃)-alkenyl, (C₁-C₇)-alkyl or (C₃-C₅)-alkinyl, which are optionally substituted by phenyl, pyridyl, furyl, thienyl or pyrryl, where the ring systems are optionally substituted up to 2 times by identical or different substituents from the group consisting of (C₁-C₃)-alkoxy, fluorine, chlorine, bromine and (C₁-C₃)-alkyl,

R² and R³ represent hydrogen or methyl,

and

D and E together form radicals of the formulae

 in which

R³¹, R³², R³³, R³⁴, R³⁵ represent hydrogen,

and their pharmaceutically acceptable salts.

Very particular preference is given to the structures listed in the table below, which can be present in racemic form or enantiomerically pure:

Moreover, we have found a process for preparing the compounds of the general formula (I) according to the invention, characterized in that

compounds of the general formula (II)

in which

D, E, R² and R³ are as defined above

 are reacted with compounds of the general formula (III),

T-A-R¹  (III)

 in which

T represents halogen, preferably bromine,

and

A and R¹ are as defined above,

in inert solvents and in the presence of a base,

and the substituent R¹ is, if appropriate, derivatized by customary methods.

The process according to the invention can be illustrated in an exemplary manner by the formula scheme below:

Suitable solvents are all inert solvents which do not change under the reaction conditions. These preferably include ethers, such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether. Particular preference is given to tetrahydrofuran.

Suitable bases are the customary inorganic or organic bases. These preferably include alkali metal hydroxides, such as, for example, sodium hydroxide or potassium hydroxide, or alkali metal carbonates, such as sodium carbonate or potassium carbonate, or sodium methoxide or potassium methoxide, or sodium ethoxide or potassium ethoxide or potassium tert-butoxide, or amides, such as sodium amide, lithium bis-(trimethylsilyl)amide, lithium diisopropylamide, or organometallic compounds, such as butyllithium or phenyllithium. Preference is given to lithium diisopropylamide and lithium bis-(trimethylsilyl)amide.

Here, the base is employed in an amount of from 1 to 5, preferably from 1 to 2 mol, based on 1 mol of the compounds of the general formula (II).

The reaction is generally carried out in a temperature range of from −78° C. to reflux temperature, preferably from −78° C. to +20° C.

The reaction can be carried out under atmospheric, elevated or under reduced pressure (for example from 0.5 to 5 bar). In general, the reaction is carried out at atmospheric pressure.

Derivatizations in the context of the invention which may preferably be mentioned are reactions at the radical R¹ with substituent groups (C₁-C₆)-alkoxy, —NR¹⁴R¹⁵, —NR¹⁶—COR¹⁷—, —NR¹⁸—CO₂R¹⁹ and —CO—NR²⁰R²¹. Starting with the carboxylic-acid-substituted aryls, these are reacted with the corresponding amines in inert solvents and in the presence of an auxiliary. Also possible is a Curtius rearrangement in the presence of (C₆H₅O)₂—PON₃. Likewise, it is possible, starting from amino-substituted aryls (R¹), to introduce the amide function via the corresponding acid chlorides in the presence of bases or via the corresponding carboxylic acids in the presence of an auxiliary.

The derivatizations can be illustrated in an exemplary manner by the following formula scheme:

The amidation is generally carried out in inert solvents in the presence of a base and a dehydrating agent.

Here, suitable solvents are inert organic solvents which do not change under the reaction conditions. These include halogenated hydrocarbons, such as dichloro-methane, trichloromethane, carbon tetrachloride, trichloroethane, tetrachloroethane, 1,2-dichloroethane or trichlorothylene, hydrocarbons, such as benzene, xylene, toluene, hexane, cyclohexane, or mineral oil fractions, nitromethane, dimethyl-formamide, acetonitrile or hexamethylphosphoric triamide. It is also possible to use mixtures of the solvents. Particular preference is given to dichloromethane.

Suitable bases for the derivatizations are the customary basic compounds. These preferably include alkali metal hydroxides or alkaline earth metal hydroxides, such as lithium hydroxide, sodium hydroxide, potassium hydroxide or barium hydroxide, alkali metal hydrides, such as sodium hydride, alkali metal carbonates or alkaline earth metal carbonates, such as sodium carbonate, potassium carbonate, or alkali metal alkoxides, such as, for example, sodium methoxide or sodium ethoxide, potassium methoxide or potassium ethoxide or potassium tert-butoxide, or organic amines, such as benzyltrimethylammonium hydroxide, tetrabutylammonium hydroxide, pyridine, triethylamine or N-methylpiperidine.

The derivatizations are generally carried out in a temperature range of from −20° C. to 150° C., preferably at from 0° C. to 25° C.

The derivatizations are generally carried out under atmospheric pressure. However, it is also possible to carry out the processes under reduced pressure or under elevated pressure (for example in a range from 0.5 to 5 bar).

When carrying out the derivatizations, the bases are generally employed in an amount of from 1 to 3 mol, preferably from 1 to 1.5 mol, based on 1 mol of the carboxylic acid in question.

Suitable dehydrating agents are carbodiimides, such as, for example, diisopropyl-carbodimide, dicyclohexylcarbodiimide or N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimide hydrochloride, or carbonyl compounds, such as carbonyldiimidazole, or 1,2-oxazolium compounds, such as 2-ethyl-5-phenyl-1,2-oxazolium-3-sulphonate, or propanephosphoric anhydride or isobutyl chloroformate or benzotriazolyloxy-tris-(dimethylamino)phosphonium hexyfluorophosphate or diphenyl phosphonamidate or methanesulphonyl chloride, if appropriate in the presence of bases, such as triethylamine or N-ethylmorpholine or N-methylpiperidine or dicyclohexylcarbo-duimide or N-hydroxysuccinimide.

Moreover, we have found a process for preparing the compounds of the general formula (I′) according to the invention

in which

A, R¹, R² and R³ are as defined above,

and

D and E together form radicals of the formulae

 in which

R³³, R³⁵, R³⁶ and R³⁸ represent hydrogen, and

R³⁴ and R³⁷ are as defined above,

 characterized in that

a compound of the general formula (I″)

 in which

A, R¹, R² R³, R³¹ and R³² are as defined above,

is isomerized in the presence of a catalyst and, if appropriate, a solvent.

The process according to the invention can be illustrated in an exemplary manner by the formula scheme below:

Suitable solvents are, for example, alcohols.

Preference is given to n-butanol.

Suitable catalysts are transition metals, such as, for example, palladium, platinum or rhodium, preferably palladium, in an amount of from 0.01 to 1 equivalent, based on the amount of the compound of the general formula (I″) used, preferably from 0.05 to 0.2 equivalents.

Very particular preference is given to palladium adsorbed on activated carbon.

The reaction is generally carried out in a temperature range from 80 to 200° C., preferably from 100 to 150° C.

The reaction can be carried out under atmospheric, elevated or under reduced pressure (for example from 0.5 to 5 bar). In general, the reaction is carried out under atmospheric pressure.

Moreover, the present invention relates to compounds of the general formula (II)

in which

R² and R³ are identical or different and represent hydrogen or (C₁-C₆)-alkyl,

and

D and E together form radicals of the formulae

 in which

R³¹, R³², R³³, R³⁴, R³⁵, R³⁶, R³⁷and R³⁸ are identical or different and represent hydrogen, phenyl or (C₁-C₆)-alkyl.

Preference is given to compounds of the general formula (II), in which

R² and R³ represent hydrogen or methyl,

and

D and E together form radicals of the formulae

 in which

R³¹, R³², R³³, R³⁴ and R³⁵ represent hydrogen.

Moreover, we have found processes for preparing the compounds of the general formula (II) according to the invention

in which

D, E, R² and R³ are as defined above,

characterized in that in

[A] compounds of the general formula (IV)

 in which

D and E are as defined above

and

R³⁹ represents (C₁-C₄)-alkyl or (C₂-C₄)-alkenyl, which are optionally substituted by phenyl,

 the ester group is selectively reduced and the reaction product is cyclized under acidic conditions, if appropriate after prior activation of the carboxyl group to give the lactone,

or

[B] compounds of the general formula (V)

 in which

D and E are as defined above

and

R⁴⁰ represents (C₁-C₄)-alkyl or (C₃-C₄)-alkenyl, which may optionally be substituted by phenyl,

 the carboxyl group is selectively reduced and the reaction product is cyclized to give the lactone,

or

[C] compounds of the general formula (VI)

 in which

D and E are as defined above,

 are initially reduced under suitable reduction conditions to give a hydroxylactone and subsequently reacted in an inert solvent with a compound of the general formula (VII),

R^(2′)—Q  (VII),

 in which

R² represents (C₁-C₆)-alkyl, and

Q represents an alkali metal halide or alkaline earth metal halide, preferably Mg—X,

 and cyclized under acidic conditions to give the corresponding lactone,

or

[D] compounds of the general formula (VI) are reacted in an inert solvent with at least two molar equivalents of a compound of the general formula (VII) and cyclized under acidic conditions to give the corresponding lactone,

or

[E] compounds of the general formula (VI) are, in an inert solvent, initially reacted with a molar equivalent of a compound of the general formula (VII), and then reacted with at least one further molar equivalent of a compound of the general formula (VIII)

R^(3′)—Q′  (VIII),

 in which

R^(3′) represents (C₁-C₆)-alkyl and

Q′ has the abovementioned meaning of Q and is identical to or different from this,

 and cyclized under acidic conditions to give the corresponding lactone.

The processes according to the invention can be illustrated in an exemplary manner by the formula schemes below:

Suitable reducing agents for the process [A] are complex metal hydrides.

Preference is given to diisobutylaluminium hydride.

Suitable solvents are inert solvents, such as, for example, methylene chloride, THF, dioxane, diethyl ether, toluene, 1,2-dichloroethane.

Preference is given to methylene chloride.

The reaction is generally carried out in a temperature range of from −40° C. to the reflux temperature of the solvent, preferably from 0° C. to 30° C.

If appropriate, the cyclization of the hydroxycarboxylic acid intermediate can be supported by activating the carboxyl group, for example using alkyl chloroformates, preferably methyl chloroformate, in the presence of a base, such as, for example, triethylamine.

A suitable method of reduction for the process [B] is a stepwise reduction by pre-activating the carboxyl group using alkyl chloroformates, preferably methyl chloroformate, in the presence of a base, such as, for example, triethylamine, followed by reduction with a complex metal hydride, such as, for example, a borohydride, preferably sodium borohydride.

Suitable solvents for the activation are inert solvents, such as diethyl ether, THF, methylene chloride. Suitable solvents for the reduction with borohydrides are, for example, alcohols, in particular methanol.

The reaction is generally carried out in a temperature range from −40° C. to 40° C., preferably from −20° C. to 30° C.

Suitable reducing agents for the process [C] are complex metal hydrides having reduced reactivity, such as, for example, lithium tris-tert-butoxyaluminohydride.

Solvents which are suitable for this purpose are inert solvents, such as, for example, diethyl ether or THF.

The reaction is generally carried out in a temperature range of from −78° C. to 0° C., preferably from −50° C. to −20° C.

Suitable inert solvents for the reaction with the compounds of the general formulae (VII) and (VIII) in processes [C] to [E] are ethers, preferably diethyl ether or THF.

The reactions are generally carried out in a temperature range of from −78° C. to 35° C., preferably at from −60° C. to 25° C.

Suitable acids for the cyclization to the lactones are, in particular, mineral acids, such as, for example, dilute aqueous sulphuric acid or hydrochloric acid.

The compounds of the general formulae (IV) and (V) are known per se or can be prepared by customary methods.

The compounds of the general formula (I) according to the invention are suitable for use as medicaments in the treatment of humans and animals.

The compounds of the general formula (I) according to the invention are suitable for modulating metabotropic glutamate receptors and therefore influence the glutamatergic neurotransmitter system.

For the purpose of the invention, a modulator of the metabotropic glutamate receptor is an agonist or antagonist of this receptor.

The compounds according to the invention are particularly suitable as modulators of the metabotropic glutamate receptor of subtype 1, very particularly as antagonists of this receptor subtype.

Owing to their pharmacological properties, the compounds according to the invention can be used, on their own or in combination with other pharmaceuticals, for the treatment and/or prevention of neuronal damage or disorders associated with pathophysiological conditions of the glutamatergic system in the central and peripheral nervous system.

For the treatment and/or prevention of neuronal damage caused, for example, by ischaemic, thromb- and/or thrombemolic and haemorrhagic stroke, conditions after direct and indirect injuries in the area of the brain and the skull. Furthermore for the treatment and/or prevention of cerebral ischaemias after surgical interventions in the brain or peripheral organs or body parts and conditions of pathological or allergic nature accompanying or preceding them, which can lead primarily and/or secondarily to neuronal damage.

Likewise, the compounds according to the invention are also suitable for the therapy of primary and/or secondary pathological conditions of the brain, for example during or after cerebral vasospasms, hypoxia and/or anoxia of previously unmentioned origin, perinatal asphyxia, autoimmune disorders, metabolic and organ disorders which can be accompanied by damage to the brain, and also damage to the brain as a result of primary brain disorders, for example convulsive conditions and artero- and/or arteriosclerotic changes. For the treatment of chronic or psychiatric conditions such as, for example, depression, neurodegenerative disorders, such as, for example, Alzheimer's, Parkinson's or Huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis, neurodegeneration due to acute and/or chronic viral or bacterial infections and multiinfarct dementia.

Moreover, they can be used as pharmaceuticals for the treatment of dementias of different origin, impaired brain performance owing to old age, memory disturbances, spinal injuries, states of pain, states of anxiety of different origin, medicament-related Parkinson's syndrome, psychoses (such as, for example, schizophrenia), brain oedema, neuronal damage after hypoglycaemia, emesis, nausea, obesity, addiction and withdrawal symptoms, CNS-mediated spasms, sedation and motor disturbances.

Furthermore, the compounds of the general formula (I) according to the invention can be used for promoting neuronal regeneration in the post-acute phase of cerebral injuries or chronic disorders of the nervous system.

They are preferably employed as pharmaceuticals for the treatment of cerebral ischaemias, craniocerebral trauma, states of pain or CNS-mediated spasms (such as, for example, epilepsy).

The modulation of substances at the metabotropic glutamate receptor (direct or indirect effect on the coupling efficiency of the glutamate receptor to G-proteins) can be examined using primary cultures of granular cells from the cerebellum. Electrophysiological measurements on these cell cultures in the “cell attached” mode show that L-type Ca²⁺-channels in this preparation are activated by mGluR1-receptors (J. Neurosci. 1995, 15, 135), whereas they are blocked by group II receptors (J. Neurosci. 1994, 14, 7067-7076). By an appropriate experimental arrangement, it is possible to monitor the modulatory effect of pharmacological test substances on glutamate receptors. Detailed examination of subtype specificity under controlled conditions can be carried out by injecting the appropriate mGluR subtype DNA into Xenopus oocytes (WO 92/10583).

Permanent Focal Cerebral Ischaemia in the Rat (MCA-O)

Under isoflurane anaesthesia, the middle cerebral artery is exposed on one side and the latter and its side branches are irreversibly sealed by means of electrocoagulation. As a result of the intervention a cerebral infarct is formed. During the operation, the body temperature of the animal is kept at 37° C. After wound closure and wearing off of the anaesthesia, the animals are again released into their cage. Substance administration is carried out according to different time schemes and via different administration routes (i.v., i.p.) after occlusion. The infarct size is determined after 7 days. To do this, the brain is removed, worked up histologically and the infarct volume is determined with the aid of a computer-assisted analysis system.

Effectiveness in the model of permanent focal cerebral ischaemia (MCA-O)

% reduction of Example infarct volume Dose^(a)) 35 38 0.01 mg/kg/h ^(a))Substance administered as intravenous continuous infusion directly up to 4 hours after the occlusion

Subdural Haematoma in the Rat (SDH)

Under anaesthesia, the animal's own blood is injected subdurally on one side. An infarct is formed under the haematoma. Substance administration is carried out according to different time schemes and via different administration routes (i.v., i.p.).

The determination of the infarct size is carried out as described in the model of permanent focal ischaemia in the rat (MCA-O).

Effectiveness in the model “Subdural haematoma in the rat (SDH)”

% reduction of Example infarct volume Dose^(a)) 35 51 0.01 mg/kg/h ^(a))Substance administered as intravenous continuous infusion directly up to 4 hours post-trauma

Using the method described in NeuroReport 1996, 7, 1469-1474, it is possible to test for antiepileptic activity.

The suitability of the compounds according to the invention for treating schizophrenia can be determined by the methods described in Science 1998, 281, 1349-1352 and Eur. J. Pharmacol. 1996, 316, 129-136.

The present invention also includes pharmaceutical preparations which, in addition to inert, non-toxic, pharmaceutically suitable auxiliaries and excipients, comprise one or more compounds of the general formula (I), or which consist of one or more active compounds of the formula (I), and processes for producing these preparations.

In these preparations, the active compounds of the formula (I) should be present in a concentration of from 0.1 to 99.5% by weight, preferably from 0.5 to 95% by weight, of the total mixture.

In addition to the active compounds of the formula (I), the pharmaceutical preparations may also comprise other pharmaceutical active compounds.

The abovementioned pharmaceutical preparations can be prepared in a customary manner by known methods, for example with the auxiliary(ies) or excipient(s).

In general, it has proved advantageous to administer the active compound(s) of the formula (I) in total amounts of about 0.01 to about 100 mg/kg, preferably in total amounts of about 1 mg/kg to 50 mg/kg, of body weight per 24 hours, if appropriate in the form of a plurality of individual administrations, to achieve the desired result.

However, if appropriate, it may be advantageous to depart from the amounts mentioned, namely depending on the type and on the body weight of the object treated, on the individual response towards the medicament, the nature and severity of the disorder, the manner of formulation and administration, and the time or interval at which administration takes place.

General Section

Mobile Phases for Chromatography

I Dichloromethane/methanol II Dichloromethane/ethanol III Cyclohexane/ethyl acetate IV Cyclohexane/dichloromethane V Butyl acetate:butanol:acetic acid:phosphate buffer (pH = 6) = 200:26:100:60

Abbreviations

DME 1,2-dimethoxyethane HMPA Hexamethylphosphoric triamide LiHMDS Lithium bistrimethylsilylamide LDA Lithium diisopropylamide MTBE Methyl tert-butyl ether THF Tetrahydrofuran MPLC Medium pressure liquid chromatography

Starting Materials

EXAMPLE 1A (3aS*,6aR*)-5-Methylidene-hexahydro-cyclopenta[c]furan-1-one

At −15° C., a solution of 2-methoxycarbonyl-4-methylidenecyclopentanecarboxylic acid (189.2 g; 1.027 mol) in THF (1 l) was admixed with triethylamine (156.6 ml; 1.130 mol) and ethyl chloroformate (18.2 ml; 1.027 mol), and the reaction mixture was stirred at room temperature for 1 h. The precipitate was filtered off with suction and the filtrate was concentrated, taken up in methanol (1 l), NaBH₄ (97.146 g; 2.568 mol) was added a little at a time at −15° C. and the mixture was stirred at room temperature for 1 h. For work-up, the mixture was admixed with 1 N HCl, saturated with NaCl and extracted with ethyl acetate. The combined organic phases were dried (Na₂SO₄) and concentrated, and the crude product was purified by chromatography.

Yield: 82.03 g (58%)

R_(f) (II, 50:1)=0.42

MS (EI): m/e=138 [M⁺]

EXAMPLE 2A (−)-(3aS,6aR)-5-Methylidene-hexahydro-cyclopenta[c]furan-1-one

Analogously to the procedure of Example 1A, the target compound was prepared from (1R,2S)-4-methylidene-2-(3-phenyl-2-propenyloxycarbonyl)-cyclopentane-carboxylic acid (31.5 g; 110.2 mmol; 97% ee; Example 1 in EP 805 145A1, p. 9).

Yield: 7.97 g (52%; 97% ee)

R_(f) (I, 80:1)=0.56

EXAMPLE 3A (+)-(3aR, 6aS)-5-Methylidene-hexahydro-cyclopentan[c]furan-1-one

At 10° C., a solution of diisobutylaluminium hydride (1.5 M in CH₂Cl₂; 17.7 ml; 26.58 mmol) was added dropwise to a solution of (1S,2R)-4-methylidene-2-allyloxy-carbonyl-cyclopentane-carboxylic acid (2.0 g; 9.61 mmol; 75% ee; Example 5 in DOS (German Published Specification) 44 00 749, p. 11+12) in dichloromethane (50 ml), and the mixture was stirred at room temperature for 1 h. The mixture was admixed with 1 N HCl and water and extracted with ethyl acetate. The combined organic phases were dried (Na₂SO₄), the solvent was removed under reduced pressure and the residue was taken up in THF (200 ml). At 0° C., triethylamine (6.59 ml; 47.57 mmol) and ethyl chloroformate (2.27 ml; 23.78 mmol) were added and the reaction mixture was allowed to stand at 8° C. for 14 h. The mixture was then admixed with ethyl acetate and water. The organic phase was washed with 10% aqueous HCl, saturated NaCl solution, 10% aqueous NaHCO₃ solution and saturated NaCl solution, dried (MgSO₄) and concentrated, and the residue was purified by MPLC.

Yield: 260 mg (20%, 89% ee)

R_(f) (I, 10:1)=0.88

EXAMPLE 4A (3S*,3aR*,6aS*)-3-Methyl-5-methylidene-hexahydro-cyclopenta[c]furan-1-one

At −40° C., a solution of 4-exomethylene-1,2-cyclopentanedicarboxylic anhydride (10.0g, 65.7 mmol; ref. DE 4400749) in THF (130 ml) was added to a solution of lithium tri-tert-butoxyaluminohydride (1M in THF, 82.16 ml), and the reaction mixture was stirred at −30° C. for 14 h. For work-up, the mixture was admixed with 1 N HCl, the THF was removed under reduced pressure and the aqueous phase was saturated with NaCl and extracted with dichloromethane. The combined organic phases were dried (MgSO₄), the solvent was removed under reduced pressure and the residue was purified by MPLC. Yield: 2.24 g.

The resulting intermediate (1 g; 6.47 mmol) in diethyl ether (15 ml) was, at 0° C., added to a solution of methylmagnesium bromide (3M in diethyl ether, 4.3 ml, 12.0 mmol), and the reaction mixture was stirred at room temperature for 2 h. The mixture was admixed with 10% aqueous HCl, stirred at room temperature and extracted with ethyl acetate, the combined organic phases were dried (Na₂SO₄), the solvents were removed under reduced pressure and the crude product was purified by MPLC.

Yield: 412 mg (33%)

R_(f) (CH₂Cl₂)=0.69

MS (DCI/NH₃): m/e=170 [M+NH₄ ⁺]

EXAMPLE 5A (3aS*,6aR*)-3,3-Dimethyl-5-methylidene-hexahydro-cyclopenta[c]furan-1 -one

At 0° C., a solution of 4-exomethylene-1,2-cyclopentanedicarboxylic anhydride (1.0 g; 6.5 mmol) in diethyl ether (40 ml) was added to a solution of methylmiagnesium bromide (3 M in diethyl ether, 6.6 ml; 19.7 mmol), and the reaction mixture was stirred at room temperature for 14 h. The mixture was admixed with 10% aqueous HCl, saturated with sodium chloride and extracted with ethyl acetate, and the combined organic phases were washed with 10% aqueous Na₂CO₃ and saturated NaCl solution and dried (Na₂SO₄). Removal of the solvents under reduced pressure gives the title compound.

Yield: 929 mg (85%)

R_(f) (I, 10:1)=0.24

MS (EI): m/e=166 [M⁺]

PREPARATION EXAMPLES EXAMPLE 1 (3aS*,6aS*)-6a-Benzyl-5-methylidene-hexahydro-cyclopenta[c]furan-1-one

At −78° C., a solution of the compound from Example 1A (90 mg, 0.65 mmol) in toluene (3 ml) was added to a solution of LiHMDS (1M in THF, 0.65 ml, 0.65 mmol) diluted with toluene (7 ml). The mixture was allowed to warm to room temperature, stirred for a further 60 min and then admixed with the alkylating agent (benzyl bromide, 89.1 mg, 0.521 mmol). After 14 h at room temperature, water (1 ml) was added, the reaction mixture was filtered through a frit filled with bituminous earth/silica gel, the solvents were removed under reduced pressure and the crude product was, if appropriate, purified by MPLC;

Yield: 81 mg (68%)

R_(f) (I, 80:1)=0.67

MS (EI): m/e=229 [M+H⁺]

The Examples 2 to 97 listed in the table below were prepared analogously to the procedure of Example 1. The alkylating agents used were the corresponding halides, aldehydes or esters.

Starting Ex. Material Yield No. Structure Ex. No. [%] Rf MS 2

1A 18 0.23(III, 50:1) 153[M+H+] 3

1A 8 0.582(I, 80:1) 210 [M+NH4+] 4

1A 66 0.73(I, 80:1) 223[M+H+] 5

2A 65 0.45(III, 5:1) 229[M+H+] 6

1A 13 0.47(III, 5:1) 235[M+H+] 7

1A 6 0.63 (CH2Cl2) 260 [M+NH4+] 8

1A 2 0.16(III, 5:1) 265[M+Na+] 9

1A 90 0.44(III, 5:1) 284 [M+CH3CN+ H+] 10

1A 79 0.44(III, 5:1) 284 [M+CH3CN+ H+] 11

1A 18 0.42(III, 5:1) 284 [M+CH3CN+ H+] 12

1A 7 0.27 (CH2Cl2) 265 [M+Na+] 13

1A 33 0.15 (CH2Cl2) 262 [M+NH4+] 14

1A 96 0.32(III, 5:1) 288 [M+CH3CN+ H+] 15

1A 96 0.31(III, 5:1) 288 [M+CH3CN+ H+] 16

1A 98 0.31(III, 5:1) 288 [M+CH3CN+ H+] 17

1A 11 0.20(III, 5:1) 361[M+H+] 18

1A 47 0.20(III, 5:1) 295 [M+CH3CN+ H+] 19

1A 53 0.29(III, 5:1) 296 [M+CH3CN+ H+] 20

1A 70 0.62(I, 80:1) 349[M+H+] 21

1A 34 0.42(III, 5:1) 274 [M+NH4+] 22

1A 71 0.44(III, 5:1) 298 M+CH3CN+ H+] 23

1A 9 0.15(III, 10:1) 281[M+Na+] 24

1A 38 0.30(III, 5:1) 300 [M+CH3CN+ H+] 25

1A 100 0.42(III, 5:1) 304 [M+CH3CN+ H+] 26

1A 96 0.34(III, 5:1) 304 [M+CH3CN+ H+] 27

1A 20 0.32(III, 5:1) 304 [M+CH3CN+ H+] 28

1A 99 0.34(III, 5:1) 306 [M+CH3CN+ H+] 29

1A 2 0.42(III, 5:1) 310 [M+CH3CN+ H+] 30

1A 21 0.35(III, 10:1) 284 [M+NH4+] 31

1A 58 0.242(III, 50:1) 272[M+] 32

1A 14 0.05(IV, 1:1) 291[M+Na+] 33

1A 2 0.42(III, 5:1) 291 [M+NH4+] 34

1A 45 0.34(III, 5:1) 296 [M+NH4+] 35

2A 42 0.60 (CH2Cl2) 296 [M+NH4+] 36

1A 5 0.24(III, 5:1) 301[M+Na+] 37

1A 1 0.58(III, 1:1) 281[M+H+] 38

1A 99 0.36(III, 5:1) 322[M+CH3CH+ H+] 39

1A 15 0.35(III, 10:1) 300 [M+NH4+] 40

1A 5 0.192(III, 10:1) 326 [M+CH3CN+ H+] 41

1A 28 0.46(III, 5:1) 302 [M+NH4+] 42

1A 59 0.66(I, 80:1) 309[M+Na+] 43

1A 41 0.12(III, 5:1) 328 [M+CH3CN+ H+] 44

1A 3 0.42(III, 4:1) 310 [M+NH4+] 45

1A 84 0.31(III, 5:1) 338 [M+CH3CN+ H+] 46

1A 80 0.31(III, 5:1) 338 [M+CH3CN+ H+] 47

1A 75 0.42(III, 5:1) 338 [M+CH3CN+ H+] 48

1A 44 0.44(III, 5:1) — 49

1A 12 0.24(III, 10:1) 314 [M+NH4+] 50

1A 25 0.82(I, 80:1) 327[M+Na+] 51

1A 53 0.21(III, 40:1) 305[M+H+] 52

1A 53 0.44(III, 5:1) 305[M+H+] 53

1A 3 0.42(III, 5:1) 348 [M+CH3CN+ H+] 54

1A 24 0.42(III, 5:1) 307[M+H+] 55

1A 31 0.19(III, 10:1) 307/309 [M+H+] 56

1A 96 0.42(III, 5:1) 348 [M+CH3CN+ H+] 57

2A 67 0.45(III, 5:1) 307/309 [M+H+] 58

1A 9 0.42(III, 5:1) 352 [M+CH3CN+ H+] 59

1A 3 0.42(III, 5:1) 352 [M+CH3CN+ H+] 60

1A 49 0.32(III, 2:1) 336[M+H+] 61

1A 15 0.78(I, 80:1) — 62

1A 17 0.42(III, 5:1) 336 [M+NH4+] 63

1A 50 0.41(III, 5:1) 338 [M+NH4+] 64

2A 52 0.45(III, 5:1) 321[M+H+] 65

1A 46 0.61 (CH2Cl2) 323/321 [M+H+] 66

1A 37 0.16(III, 10:1) 338 [M+NH4+] 67

1A 26 0.42(III, 5:1) 340/342 [M+NH4+] 68

1A 39 0.27(III, 5:1) 370 [M+CH3CN+ H+] 69

1A 35 0.42(III, 5:1) — 70

1A 3 0.42(III, 5:1) 372 [M+CH3CN+ H+] 71

1A 51 0.22(IV, 1:1) 355[M+Na+] 72

1A 33 0.42(III, 5:1) 380 [M+CH3CN+ H+] 73

1A 40 0.42(III, 5:1) 380 [M+CH3CN+ H+] 74

1A 25 0.75(III, 50:1) 362[M+H+] 75

1A 62 0.20(IV, 5:1) 347[M+H+] 76

1A 38 0.42(III, 5:1) 396 [M+CH3CN+ H+] 77

1A 23 0.26(III, 10:1) 372 [M+NH4+] 78

1A 17 0.42(III, 5:1) 374/376 [M+NH4+] 79

1A 30 0.42(III, 5:1) 398 [M+CH3CN+ H+] 80

1A 4 0.42(III, 5:1) 380 [M+NH4+] 81

1A 16 0.42(III, 5:1) 409[M+H+] 82

1A 5 0.39(III, 5:1) 351[M+H+] 83

1A 5 0.22(III, 5:1) 337[M+H+] 84

1A 29 0.24(III, 10:1) 298 [M+NH4+] 85

1A 19 0.27(III, 10:1) 287[M+H+] 86

1A 9 0.30(III, 10:1) 293[M+H+] 87

1A 12 0.11(III, 10:1) 458 [M+NH4+] 88

1A 42 0.25(III, 10:1) 269[M+H+] 89

2A 55 0.34(III, 5:1) — 90

2A 62 0.47(III, 5:1) 310 [M+H+H3C CN+] 91

2A 38 0.30(III, 5:1) — 92

2A 52 0.18(III, 5:1) 304 [M+NH4+] 93

2A 74 0.34(III, 5:1) 314 [M+H3CCN +H+] 94

2A 66 0.36(III, 5:1) 326 [M+H3CCN +H+] 95

2A 56 0.39(III, 5:1) 288 [M+H3CCN +H+] 96

1A 40 0.39(III, 5:1) 346 [M+NH4+] 97

1A 10 0.35(III, 10:1) 300 [M+NH4+]

EXAMPLE 98 (3aS*,6aS*)-6a-(4-Allyloxycarbonylaminobenzyl)-5-methylene-hexahydro-cyclopenta[c]-furan-1-one

A mixture of the compound from Example 124 (2.02 g; 7.5 mmol), allyl alcohol (4.3 g, 74.29 mmol), diphenylphosphoryl azide (2.25 g, 8.17 mmol), diazabicyclo-octane (DABCO, 0.17 g; 1.5 mmol) and triethylamine (0.9 g, 8.92 mmol) in toluene (70 ml) was stirred under reflux for 48 h. The reaction mixture was admixed with 2 g of silica gel, the solvent was removed under reduced pressure and the residue was purified by MPLC.

Yield: 1.29 g (53%)

R_(f) (III, 5:1)=0.23

MS (DCI): m/e=345 [M+NH₄ ⁺]

The Examples 99 to 103 listed in the table below were prepared analogously to the procedure of Example 98:

Ex. No. Structure Yield R_(f) MS  99

97 0.75 (III, 1:1) / 100

25 0.35 (III, 2:1) / 101

12 0.44 (III, 2:1) / 102

68 0.50 (III, 2:1) / 103

27 0.53 (III, 2:1) /

EXAMPLE 104 (3aS*,6aS*)-6a-(4-Aminobenzyl)-5-methylidene-hexahydro-cyclopenta[c]furan-1-one

Example 98 (1.275 g; 3.96 mmol) was added to a solution of tris(dibenzylidene-acetone)dipalladium(0) (181 mg; 0.198 mmol), bis(diphenyl-phosphino)ethane (315 mg; 0.79 mmol) and dimedone (4.44 g; 31.65 mmol) in THF (320 ml) and the reaction mixture was heated under reflux for 1 hour. The reaction mixture is poured into 1 N HCl and the aqueous phase is washed with ethyl acetate (2×), then adjusted to pH=9-10 and extracted with ethyl acetate (3×). The combined extracts are washed with saturated NaCl solution and dried (MgSO₄) and the solvent is removed under reduced pressure.

Yield: 0.770 g (80%)

R_(f) (III, 1:1)=0.42

The following compounds were prepared analogously:

Ex. No. Structure Yield R_(f) 105

83 0.42 (II, 1:1)

EXAMPLE 106 (3aS*,6aS*)-6a-(4-Acetylaminobenzyl)-5-methylidene-hexahydro-cyclopenta[c]furan-1-one

Triethylamine (12 μl, 0.080 mmol) and acetyl chloride (3.1 mg; 0.039 mmol) were added to a solution of the compound from Example 104 (10 mg; 0.036 mmol) in dichloromethane (5 ml), and the reaction mixture was stirred at room temperature for 20 h. For work-up, a saturated NaHCO₃ solution (1 ml) was added and the mixture was filtered through a frit filled with bituminous earth/silica gel and the product was eluted with dichloromethane/ethanol.

Yield: 12.2 mg (quant.)

R_(f) (II, 50:1)=0.18

MS (ESI): m/e=286 [M+H⁺]

The following compounds were prepared analogously:

Ex. No. Structure Yield R_(f) MS 107

quant. 0.12 (II, 100:1) 376 [M + H⁺] 108

quant. 0.10 (II, 100:1) 328 [M + H⁺]

EXAMPLE 109 (3aS′″*,6a′″S*)-N-[3-(5-Methylidene-hexahydro-cyclopenta[c]furan-1-on-6a-yl-methyl)-phenyl]-morpholine

A mixture of triethylamine (208 μl; 1.5 mmol), morpholine (131 μl ; 1.5 mmol) and the compound from Example 65 (321 mg; 1.0 mmol) in dichloromethane (1 ml) were stirred at room temperature for 14 h. The mixture was concentrated and the crude product was purified by MPLC.

Yield: 230 mg (70%)

R_(f) (I, 40:1)=0.25

MS (DCI/NH₃): m/e=328 [M+H⁺]

The Examples 110 to 116 listed in the table below were prepared analogously to Example 109:

Starting Ex. material Yield No. Structure Ex. No. (%) R_(f) MS 110

66 33 0.29 (I, 40:1) 328 [M + H⁺] 111

65 26 0.31 (I, 40:1) 340 [M + H⁺] 112

66 15 0.22 (I, 40:1) 340 [M + H⁺] 113

65 79 0.21 (I, 40:1) 403 [M + H⁺] 114

66 76 0.27 (I, 40:1) 403 [M + H⁺] 115

65 55 0.17 (I, 40:1) 436 [M + H⁺] 116

66 55 0.13 (I, 40:1) 436 [M + H⁺]

EXAMPLE 117 AND EXAMPLE 118 (3aS*,6aS*)-5-Methyl-6a-naphth-2-ylmethyl-3,3a,6,6a-tetrahydro-cyclopenta[c]-furan-1-one (Example 117) and (3aS*,6aS*)-5-methyl-6a-naphth-2-ylmethyl-3,3a,4,6a-tetrahydro-yclopenta[c]furan-1 -one (Example 118)

A mixture of the compound from Example 34 (370 mg, 1.33 mmol) and Pd-C (10%, 10 370 mg) in n-butanol (10 ml) was stirred under reflux for 48 h. Filtration, distillative removal of the solvent under reduced pressure and purification of the crude product by MPLC gave the title compound;

Yield: 155 mg (42%, Example 117)

R_(f) (III, 5:1)=0.36

MS (EI): m/e=279 [M+H⁺]

Yield: 75 mg (21%, Example 118)

R_(f) (III, 5:1)=0.30

MS (EI): m/e=301 [M+Na⁺]

EXAMPLE 119 AND EXAMPLE 120 (3aS*,3R*,6aS *)-3-Methyl-5-methylidene-6a-naphth-2-ylmethyl-hexahydro-cyclo-penta(c)furan-1-one and (3aS*,3S*,6aS*)-3-methyl-5-methylene-6a-naphth-2-yl-methyl-hexahydro-cyclopenta(c)furan-1 -one

Analogously to the procedure of Example 1, the title compounds were prepared from the compound from Example 4A (200 mg, 1.314 mmol).

Yield: 309 mg (93%, mixture of the diastereomers)

R_(f) (CH₂Cl₂)=0.53

MS (DCI)/NH₃): m/e=310 [M+NH₄ ⁺]

The diastereomers were separated by HPLC (Kromasil 100 C 18, acetonitrile/water 1:1)

EXAMPLE 121

Diastereomer A, Fraction 1.

EXAMPLE 122

Diastereomer B, fraction 2.

EXAMPLE 123 (3aS*,6aS*)-3,3-Dimethyl-5-methylidene-6a-naphth-2-ylmethyl-hexahydro-cyclopenta[c]furan-1 -one

Analogously to the procedure of Example 1, the title compound was prepared from the compound from Example 5A (100 mg, 0.6 mmol);

Yield: 116 mg (63%)

R_(f) (I, 10:1)=0.47

MS (ESI): m/e=307

EXAMPLE 124 (3a″S*,6″a)-4-(5-Methylidene-hexahydro-cyclopenta[c]furan-1-on-6a-ylmethyl)-benzoic acid

A solution of the compound from Example 43 (2.26g, 7.89 mmol) in THF (100 ml) and aqueous NaOH (1 M, 127 ml) was stirred at room temperature for 4 h. The mixture was adjusted to pH=2 using 1 N aqueous HCl, stirred for 1 h, saturated with NaCl and extracted with ethyl acetate. The combined organic phases were dried (Na₂SO₄) and the solvents were removed under reduced pressure;

Yield: 2.14g (quant.)

R_(f) (II, 10:1)=0.47

EXAMPLE 125 (3a″S*,6a″S*)-3-(5-Methylidene-hexahydro-cyclopenta[c]furan-1-on-6a-ylmethyl)-benzoic acid

Analogously to Example 124, the title compound was prepared from Example 42 (2.30 g, 8.03 mmol);

Yield: 1.38 g (63.1%)

R_(f) (II; 10:1)=0.45

MS (DCI/NH₃): m/e=290 [M+NH₄ ⁺]

EXAMPLE 126 (3a″S,6a″S)-4-(5-Methylidene-hexahydro-cyclopenta[c]furan-1-on-6a-ylmethyl)-benzoic acid

A solution of the compound from Example 92 (2.2 g, 7.68 mmol) in THF (100 ml) and aqueous NaOH (1 M, 127 ml) was stirred at room temperature for 4 h. The mixture was adjusted to pH=2 using 1 N aqueous HCl, stirred for 1 h, saturated with NaCl and extracted with ethyl acetate. The combined organic phases were dried (Na₂SO₄) and the solvents were removed under reduced pressure;

Yield: 2.1 g (quant.)

EXAMPLE 127 (3a″S*,6a″S*)-1-[(5-Methylidene-hexahydro-cyclopenta[c]furan-1-on-6a-ylmethyl)-benzoyl]4-phenylpiperazine

A mixture of the compound from Example 124 (50 mg, 0.184 mmol), N-phenyl-piperazine (32.77 mg, 0.202 mmol), 1-ethyl-3-(3′-dimethylamino)propyl)-carbodiimide hydrochloride (38.7 mg, 0.202 mmol) and triethylamine (18.6 mg, 0.184 mmol) in dichloromethane (10 ml) was stirred at room temperature for 20 h. For work-up, 10% aqueous KHSO₄ (1 ml) was added, the reaction mixture was filtered through a frit filled with bituminous earth/silica gel, the solvents were removed under reduced pressure and the crude product was purified by flash chromatography;

Yield: 90 mg (quant.)

R_(f) (II, 20:1)=0.19

MS (ESI): m/e=417 [M+H⁺]

Analogously to the procedure of Example 127, the Examples 128 to 177 listed in the table below were prepared starting from Examples 124 or 124, and the Examples 178 to 197 starting from Example 126:

HPLC Starting area Ex. Material Yield MW % at MS No. Structure Ex. No. [%] Rf MS [g/mol] 210 nm [M +H⁺] 128

124 79 0.16 (II,20:1) 312 [M+H+] 129

125 81 0.21 (II,20:1) 312 [M+H+] 130

125 71  0.313 (II,20:1) 314 [M+H+] 131

124 60 0.06 (II,20:1) 316 [M+H+] 132

125 51 0.06 (II,20:1) 316 [M+H+] 133

124 77 0.19 (II,20:1) 326 [M+H+] 134

124 75 0.24 (II,20:1) 326 [M+H+] 135

125 85 0.20 (II,20:1) 326 [M+H+] 136

125 78 0.21 (II,20:1) 326 [M+H+] 137

124 27 0.24 (III,4:1) 342 [M+H+] 138

125 35 0.25 (II,20:1) 368 [M+H+] 139

124 70 0.22 (II,20:1) 376 [M+H+] 140

125 91 0.23 (II,20:1) 376 [M+H+] 141

124 59 0.25 (II,20:1) 392 [M+H+] 142

125 66 0.25 (II,20:1) 392 [M+H+] 143

124 82 0.21 (II,20:1) 417 [M+H+] 144

124 77 0.29 (II,20:1) 431 [M+H+] 145

125 58  0.213 (II,20:1) 431 [M+H+] 146

124 67 0.33 (II,20:1) 440 [M+H+] 147

125 81 0.43 (II,20:1) 440 [M+H+] 148

124 53 0.05 (II,20:1) 445 [M+H+] 149

125 52 0.04 (II,20:1) 445 [M+H+] 150

124 93 0.25 (II,20:1) 452 [M+H+] 151

125 71 0.28 (II,20:1) 452 [M+H+] 152

124 341.4542 97 342 153

124 449.5518 97 450 154

124 376.4593 92 377 155

124 375.4718 96 376 156

124 361.4447 96 362 157

124 341.4542 96 342 158

124 367.4925 95 368 159

124 430.3347 96 430 160

124 409.9168 95 410 161

124 440.3407 96 440 162

124 339.4383 96 340 163

124 444.3618 95 444 164

124 362.4322 97 363 165

124 377.4441 98 378 166

124 369.5084 94 370 167

124 347.4176 94 348 168

124 475.5958 94 476 169

124 399.4354 96 400 170

124 367.3714 93 368 171

124 313.4001 96 314 172

124 329.3995 99 330 173

124 311.3841 95 312 174

124 327.4272 94 328 175

124 379.5036 95 380 176

124 447.9662 64 448 177

124 354.4309 51 355 178

327.43 85 369 179

327.43 92 369 180

367.49 89 409 181

409.92 94 451 182

405.50 88 447 183

435.52 96 477 184

357.45 91 358 185

351.41 89 393 186

444.36 79 485 187

405.50 93 447 188

447.54 91 448 189

389.50 90 431 190

454.37 90 495 191

405.50 93 447 192

435.52 97 436 193

313.40 83 355 194

403.53 93 445 195

405.54 57 447 196

362.43 94 363 197

362.43 98 363

EXAMPLE 198 Isopropyl (3a″S*,6a″S*)-4-(5-methylidene-hexahydro-cyclopenta[c]furan-1-on-6a-ylmethyl)-benzoate

At room temperature, triethylamine (51 μl, 0.367 mmol) and methanesulphonyl chloride (14.2 μl, 0.184 mmol) were added to a solution of the compound from Example 125 (50.0 mg, 0.184 mmol) in dichloromethane (2 ml). After 1 h, 2-propanol (10.6 μl, 0.138 mmol) and dimethylaminopyridine (4.5 mg, 0.037 mmol) were added, and the mixture was stirred at room temperature for another 20 h. For work-up, the mixture was admixed with 10% aqueous NaHCO₃ solution (1 ml) and filtered through a frit filled with bituminous earth/silica gel, the solvents were removed and the crude product was purified by chromatography;

Yield: 19 mg (32%)

R_(f) (II, 100:1)=0.47

MS (ESI): m/e=337 [M+Na^(+])

The Examples 199 to 209 listed in the table below were prepared analogously to the procedure given above.

Starting Ex. Material Yield No. Structure Ex. No. [%] Rf MS 199

124 49 0.43 (II,100:1) 342 [M+CH3CN+H+] 200

125 53 0.61 (II,100:1) 349 [M+H+] 201

124 49 0.90 (II,100:1) 364 [M+H+] 202

124 64 0.62 (II,100:1) 384 [M+H+] 203

125 61 0.27 (II,20:1) — 204

124 71 0.63 (II,100:1) 386 [M+H+] 205

124 79 0.54 (II,100:1) 411 [M+Na+] 206

124 19 0.60 (II,100:1) 403 [M+H+] 207

124 50 0.43 (II,100:1) [M+Na+] 208

125 62 0.46 (II,100:10 424 [M+NH4+] 209

124 56 0.41 (II,100:1) 450 [M+H+]

The Examples 210 to 214 listed in the table below were prepared analogously to the procedure of Example 98:

Starting Ex. Material Yield MS No. Structure Ex. No. (%) R_(f) [M+NH4⁺] 210

124 56 0.80 (III,1:1) 361 211

124 45 0.52 (III,2:1) 347 212

124 44 0.48 (III,2:1) 333 213

124 15 0.51 (III,2:1) 342 214

126 64 0.23 (III,5:1) 345

The Examples 215 to 231 listed in the table below were prepared analogously to the procedure of Example 1:

Starting Ex. Material Yield No. Structure Ex. No. (%) R_(f) MS 215

1A 30 0.52 (III;5:1) 404 [M+H⁺] 216

1A 29 0.61 (CH₂Cl₂) 342 [M+H⁺] 217

1A 15 0.52 (I,80:1) 348 [M+H⁺] 218

1A  5 0.17 (I,80:1) 269 [M+H⁺] 219

1A 11 0.47 (III,5:1) 339 [M+H⁺] 220

1A 30 0.20 (IV,5:1) 404 [M+NH₄ ⁺] 221

1A 20 0.50 (IV,1:1) 322 [M+Na⁺] 222

1A 35 0.82 (I,80:1) 227 [M+NH₄ ⁺] 223

1A 18 0.42 (III,50:1) 339 [M+NH₄ ⁺] 224

2A 40 0.16 (CH₂Cl₂) — 225

1A  9 0.62 (CH₂Cl₂) 310 [MN+NH₄ ⁺] 226

1A 31 0.35 (CH₂Cl₂) 285 [M+H⁺] 227

1A  7 0.24 (III,100:1) 329 [M+H⁺] 228

1A 15 0.52 (III,5:1)^(a)) 404 [M+H⁺] 229

1A 15 0.52 (III;5:1)^(b)) 404 [M+H⁺] 230

1A 25 0.31 (I,40:1) 347 [M+H⁺] 231

2A 52 0.42 (I,40:1) 339 [M+H⁺] ^(a))Diastereomer A: fraction 1 (HPLC, Kromasil 100C 18, methanol/H₂O 65:35) ^(b))Diastereomer B: fraction 2 (HPLC, Kromasil 100C 18, methanol/H₂O 65:35)

The Examples 232 to 255 listed in the table below were prepared analogously to the compound from Example 106:

Ex. HPLC area No. Structure MW (g/mol) % at 210 nm Mz+H 232

353.44 92 354 233

299.37 75 300 234

311.38 96 312 235

327.42 98 328 236

337.37 97 338 237

339.43 89 340 238

343.38 96 344 239

367.49 88 368 240

391.47 97 392 241

391.47 97 392 242

391.47 95 392 243

403.52 91 404 244

405.54 92 244 245

421.49 82 422 246

421.49 95 422 247

422.44 6 423 248

455.55 61 456 249

438.53 16 439 250

486.35 49 486 251

381.86 95 382 252

381.86 94 382 253

381.86 94 382 254

397.47 92 398 255

397.47 98 398

The compounds listed in the table below were prepared analogously to Example 106:

Ex. Yield No. Structure (%) MS 256

87 362 [M+H⁺] 257

80 409 [M+H₃CCN+H⁺] 258

97 392 [M+H⁺]

EXAMPLE 259 N[(3a″S*,6a″S)-4-(5-Methylidene-hexahydro-cyclopenta[c]furan-1-on-6a-ylmethyl-phenyl]-4-methylpentanecarboxamide

At 0° C., N,N-dimethylaminopyridine (10.1 mg, 0.09 mmol), 1-ethyl-3-(3′-dimethyl-amino)propyl)-carbodiimide hydrochloride (17.3 mg, 0.09 mmol) and 4-methyl-pentanecarboxylic acid (10.5 mg, 0.09 mmol) were added to a solution of the compound from Example 104 (20.0 mg, 0.082 mmol) in dichloromethane (5 ml), and the reaction mixture was stirred at room temperature for 6 hours. For work-up, 1 M aqueous HCl was added (0.7 ml), the mixture was filtered, with dichloromethane, through a frit filled with bituminous earth/silica gel, the filtrate was admixed with 10% aqueous NaHCO₃ (0.7 ml) and filtered once more through a frit filled with bituminous earth, and the solvent was removed under reduced pressure.

Yield: 27.6 mg (98%)

R_(f) (III, 2:1)=0.38

MS(ESI): m/e=342 [M+H⁺]

EXAMPLE 260 (3aS*,6aS*)-6a-(4-(2-Methylpropylaminobenzyl)-5-methylidene-hexahydro-cyclo-penta[c]furan-1-one

A solution of the compound from Example 104 (15 mg, 0.062 mmol), 2-methyl-propanal (4.5 mg, 0.062 mmol) in methanol/acetic acid (3:1, 1.2 ml) was stirred at room temperature for 20 minutes and then admixed with sodium cyanoborohydride (5.0 mg, 0.08 mmol) in methanol (0.6 ml). After 20 hours, the mixture was admixed with ether and the organic phase was washed with sat. NaHCO₃ and dried (MgSO₄).

The residue was purified by chromatography.

Yield: 3.7 mg (20%)

R_(f) (II, 50:1)=0.35

MS (ESI): m/e=300 [M+H⁺]

EXAMPLE 261 (3aS*,6aS*)-6a-(4-Hydroxybenzyl)-5-methylidene-hexahydro-cyclopenta[c]furan-1-one

A mixture of the compound from Example 279 (192 mg, 0.59 mmol), K₂CO₃ (486 mg, 3.52 mmol) in water (4.7 ml) and methanol (7.1 ml) was stirred at room temperature for 30 minutes. The mixture was adjusted to pH=2 using 1 N aqueous HCl, saturated with NaCl and extracted with ethyl acetate. The combined organic phases was dried (Na₂SO₄) and the solvents were removed under reduced pressure.

Yield: 157 mg (quant.)

R_(f) (III, 2:1)=0.31

MS (ESI): m/e=286 [M+H⁺]

EXAMPLE 262 (3aS*,6aS*)-6a-(4-(3-Methylbutyloxy)benzyl)-5-methylidene-hexahydro-cyclopenta[c]furan-1-one

A mixture of the compound from Example 261 (13.3 mg, 0.054 mol), 1-bromo-3-methylbutane (6.8 mg, 0.045 mmol), Cs₂CO₃ (44.4 mg, 0.136 mmol) in dimethoxyethane (5 ml) was stirred at 75° C. for 48 hours. For work-up, the mixture was admixed with dichloromethane and 1 M aqueous NaOH and filtered through a frit filled with bituminous earth, the solvent was removed under reduced pressure and the residue was purified by chromatography.

Yield: 2.8 mg (16%)

R_(f) (III, 5:1)=0.49

LCMS: m/e=356 [M+H₃CCN+H⁺]

EXAMPLE 263 AND 264

N-[(3a″R*, 6a″R*)-4-(5-Methylidene-hexahydro-cycopenta[c]furan-1-on-6a-yl-methyl)-phenyl]-(3-methoxyphenyl)acetamide (264) and

N-[(3a″S*, 6a″S*)-4-(5-Methyl-3,3a,6,6a-tetrahydro-cyclopenta[c]furan-1-on-6a-yl-methyl)-phenyl]-(3-methoxyphenyl)acetamide (265)

The compound from Example 104 and 3-methoxyphenylacetyl chloride were reacted analogously to the procedure of Example 106. The crude product was separated into the enantiomers by HPLC (Chiralpak AS, ethanol/iso-hexane 20:80).

Fraction I (Example 265): Enantiomer A, [α]_(D) ²⁰=−46° (c=0.473, CHCl₃)

Fraction II: not identified

Fraction III (Example 264): Enantiomer A, [α]_(D) ²⁰=−22.2° (c=0.200, CHCl₃)

Fraction IV (Example . . . ): Enantiomer B

The compounds listed in the table were prepared analogously to the procedure of Example 1:

Starting Material Yield Rf (cyclohexane/ MS (Cl) Ex. Structure Ex. No. [%] ethyl acetate 3:1) [M⁺ + 1] 265

1A 9.9 0.50 303 266

1A 3.5 0.51 319 267

1A 6.8 0.42 337 268

1A 10.2 0.63 335 269

1A 29.2 0.46 309 270

1A 15.4 0.54 293 271

1A 9.1 0.52 364 272

1A 8.2 0.39 343 273

1A 21.0 0.35 310 274

1A 10.5 0.36 343 275

1A 13.0 0.46 309

Prodedure Ex. Yield Starting analogous No. Structure % Material to Ex. Rf MS 276

39 1A 1 0.5 (CH2Cl2) 324 [M+NH4+] 277

22 1A 1 0.50 (II,1:1) 382/384 [M+NH4+] 278

17 1A 1 0.53 (III,2:1) 382/384 [M+NH4+] 279

30 1A 1 0.20 (III,5:1) 280

43 1A 1 407 [M+H*]

The examples listed in the table below were prepared analogously to the procedures mentioned.

Procedure Ex. Yield Starting analogous No. Structure % Material to Ex. Rf MS 281

30 124 98 0.23 (II,20:1) 401 [M+H+9] 282

27 124 98 0.47 (III,20:1) 330 [M+H+] 283

26 318 98 0.36 (I,40:1) 336 [M+H+] 284

20 318 98 0.34 (I,40:1) 351 [M+NH4+] 285

88 124 98 0.23 (III,5:1) 370 [M+H+] 286

73 125 98 0.15 (CH2Cl2) 287

56 327 98 0.54 (III,1:1) 423/425 [M+NH4+] 288

73 318 127 0.43(I,40:1) 332 [M+H+] 289

91 318 127 0.46 (I,40:1) 368 [M+H+] 290

92 318 127 0.45 (I,40:1) 334 [M+H+] 291

93 318 127 0.37 (I,40:1) 320 [M+H+] 292

98 124 127 0.20 (III,2:1) 383 [M+H3CCN+H+] 293

quant. 124 127 0.37 (I,40:1) 294

72 327 127 0.79 (I,10:1) 509/511 [M+H3CCN+H+] 295

66 327 127 0.79 (I,10:1) 481/483 [M+H3CCN+H+] 296

47 327 127 0.66 (I,10:1) 421/423 [M+H3CCN+H+] 297

59 327 127 0.77 (I,10:1) 459/461 [M+H3CCN+H+] 298

91 104 259 0.38 (II,2:1) 430 [M+H+] 299

 7 325 106 0.43 (III,1:1) 374 [M+H+] 300

 7 325 106 0.31 (III,1:1) 398 [M+H+] 301

 7 325 106 0.29 (III,1:1) 318 [M+H+] 302

17 325 106 0.22 (III,1:1) 306 [M+H+] 303

73 124 127 0.21 (II,20:1) 392 [M+H+] 304

17 326 106 0.38 (III,1:1) 392 [M+H+] 305

86 326 259 0.35 (III,1:1) 392 [M+H+] 306

41 105 259 0.40 (III,1:1) 307

80 105 259 0.33 (III,1:1) 308

53 105 259 0.48 (III,1:1) 309

64 105 259 0.38 (III,1:1) 310

18 105 259 0.17 (III,1:1) 437 [M+H+] 311

33 105 259 0.04 (III,1:1) 312

95 310 261 0.58 (I,10:1) 395 [M+NH4+] 313

27 104 259 498 [M+H+] 314

26 104 259 453 [M+H+] 315

 7 104 259 478 [M+H+] 316

28 104 259 438 [M+H+] 317

quant. 104 259 0.26 (II,50:1) 422 [M+H+] 318

98 1A 1(alkyla- tion) 124(hy- drolysis of the ester) 296 [M+NH4+] 319

98 104 260 0.61 (II,20:1) 405 [M+H3CCN+H+] 320

35 104 260 0.25 (III,2:1) 389 [M+H3CCN+H+] 321

53 104 260 0.62 (III,2:1) 376 [M+H+] 322

79 313 261 0.52 (I,10:1) 456 [M+H+] 323

69 314 261 0.4 (I,10:1) 454 [M+H+] 324

83 316 261 0.51 (I,10:1) 437 [M+H3CCN+H+] 325

quant. 284 104 0.33 (III,1:1) — 326

 5 286 104 0.32 (III,1:1) — 327

quant. 277 124 — 351 [M+H+] 328

40 1A 1 0.49 (III,2:1) 346 [M+NH4+] 329

83 328 261 0.31 (II,20:1) 262 [M+NH4+] 330

28 1A 1 0.39 (CH2Cl2) 321 [M+NH4+] 331

quant. 330 124 — 307 [M+H+] 332

1 1A 333

332 261 334

329 262 335

quant. 280 261 0.35 (II,20:1) — 336

90 331 127 465 [M+H+H3CCN]+ 337

87 331 127 437 [M+H3CCN+H]+ 338

98 331 127 387 [M+H3CCN+H]+ 339

78 331 127 417 [M+H3CCN+H]+ 340

63 287 104 — 363/365 [M+H3CCN+H+] 341

41 340 259 0.42 (III,1:1) 487/489 [M+H+] 342

41 1A 1 0.35 (CH2Cl2) — 343

96 105 259 0.37 (III,1:1) 422 [M+H+] 344

79 342 261 0.21 (CH2Cl2) —

The Examples listed in the table below were prepared analogously to the procedure of Example 127.

Ex. Molecular weight No. Structure Formula [g/mol] Mz + H 345

C20 H25 N O3 327.4272 328 346

C21 H27 N O3 341.4543 342 347

C25 H26 Cl N O3 423.9439 424 348

C25 H27 N O4 405.4982 406 349

C24 H24 Cl N O4 425.9162 426 350

C25 H26 Cl N O4 439.9433 440 351

C23 H24 N2 O3 376.4594 377 352

C23 H24 N2 O3 376.4594 377 353

C24 H25 N O4 391.4712 392

The compounds listed in the table were prepared analogously to the procedure of Example 259.

Ex. Molecular weight No. Structure Formula [g/mol] M + H 354

C24H31NO3 381.51957 382 355

C25H27NO3 389.49884 390 356

C25H27NO3 389.49884 390 357

C28H33NO3 431.58011 432 358

C25H26N2O5 434.49637 435 359

C24H25NO3 375.47175 376 360

C24H25NO3 375.47175 376 361

C23H22FNO3 379.43509 380 362

C23H22BrNO3 440.34069 440 363

C24H25NO3 375.47175 376 364

C27H25NO3 411.5052 412 365

C23H21BrClNO3 474.78572 474 366

C27H31NO3 417.55302 418 367

C23H18F5NO3 451.39681 452 368

C27H25NO3 411.5052 412 369

C23H21Cl2NO3 430.33472 430 370

C25H426ClNO3 423.94387 424 371

C23H22INO3 487.34109 488 372

C20H23NO4 341.41061 342 373

C2OH18BrNO4 416.27476 416 374

C21H22N2O4 366.42049 367 375

C21H21NO3S 367.47042 368 376

C23H29NO3 367.49248 368 377

C23H22BrNO3 440.34069 441 378

C22H20BrNO3 426.3136 426 379

C21H20CINO3S 401.91545 402 380

C21H21NO3S 367.47042 368 381

C23H20Cl3NO3 464.77975 464 382

C25H26ClNO3 423.94387 424 383

C24H25NO4 391.47115 392 384

C23H21Cl2NO3 430.33472 430 385

C24H23Cl2NO3 444.36181 444 386

C23H22N2O5 406.44219 407 387

C24H25NO5 407.47055 408 388

C24H25NO4 391.47115 392 389

C23H22BrNO3 440.34069 441 390

C23H22ClNO3 395.88969 396 391

C24H25NO3 375.47175 376 392

C25H27NO3 389.49884 390 393

C24H25NO5 407.47055 408 394

C23H23NO4 377.44406 378 395

C23H29NO3 367.49248 368 396

C22H27NO3 353.46539 354 397

C25H27NO4 405.49824 406 398

C21H23N3O3 365.43576 366 399

C24H25NO4 391.47115 392 400

C29H27NO4 453.54284 454 401

C24H25NO4 391.47115 392 402

C25H25NO5 419.4817 420 403

C25H25NO5 419.4817 420 404

C25H24N403 428.49503 429 405

C26H25N3O3 427.50745 428 406

C25H27NO4 405.49824 406 407

C27H31NO4 433.55242 434 408

C27H31NO4 433.55242 434 409

C27H29NO4 431.53648 432 410

C28H33NO4 447.57951 448 411

C27H31NO4 433.55242 434 412

C25H27NO4 405.49824 406 413

C25H27NO5 421.49764 422 413a

C30H29NO3 451.57053 452 414

C21H27NO3 341.45424 342 415

C23H22ClNO3 395.8897 396 416

C23H22N2O5 406.4422 407 417

C23H22BrNO3 440.3407 441 418

C23H22FNO3 379.4352 380 419

C26 H29 N O4 419.5254 419 420

C23H22ClNO3 395.8897 396 421

C25 H27 N O5 421.4977 422 422

C25 H27 N O3 389.4988 390 423

C24H23F2NO3 411.4526 412 424

C23H21ClFNO3 413.8802 414 425

C23H21ClFNO3 413.8802 414 426

C23H21Cl2NO3 430.3347 430 427

C21H21NO3S 367.47042 368 428

C21 H 21 N O3 S 367.4704 368 429

C29 H27 N O3 437.5435 438 430

C23 H23 N O4 377.4441 378 431

C25 H27 N O5 421.4977 422 432

C27H31NO4 433.55242 434 433

C25 H27 N O3 389.4988 390 434

C25 H27 N O4 405.4982 406 435

C24H24ClNO3 409.9168 410 436

C25H27NO3 389.4988 390 437

C25 H27 N O4 405.4982 406 438

C24H24ClNO3 409.9168 410 439

C26 H29 N O5 435.5248 436 440

C22 H22 N2 O3 362.4323 363

EXAMPLE 441 N[(3a″S* ,6a″S)-4-(5-Methylidene-hexahydro-cyclopenta[c]furan-1-on6a-ylmethyl)]-phenyl-N′-(isopropyl)-urea

A solution of the compound from Example 104 (20 mg, 0.084 mmol) and isopropyl isocyanate (7.8 mg, 0.092 mmol) in toluene (3 ml) was stirred at room temperature for 24 hours. For work-up, ethyl acetate (3 ml), dichloromethane (2 ml) and 1 M aqueous HCl (0.6 ml) were added, the mixture was filtered through a frit filled with bituminous earth and the solvents were removed under reduced pressure.

Yield: 7.2 mg (26%)

R_(f) (II, 2:1)=0.18

MS (ECI)=329 [M+H⁺]

The compounds listed in the table were prepared analogously to the procedure of Example 441.

Molecular weight Ex. No Structure Formula [g/mol] M + H 442

C20 H26 N2 O3 342.4418 343 443

C19 H24 N2 O3 328.4147 329 444

C18 H22 N2 O3 314.3877 315

The compounds listed in the table below were prepared analogously procedure of Example 262.

Molecular weight Ex. No. Structure Formula [g/mol] M + H 445

C17 H20 O3 272.3472 273 446

C18 H22 O3 286.3743 287 447

C19 H24 O3 300.4013 301

The compounds listed in the table were prepared analogously to the procedure of Example 262, starting from Example 335.

Molecular weight Ex. No. Structure Formula [g/mol] Mz 448

C19 H23 Br O3 379.2974 378 449

C17H19BrO3 351.24318 350 450

C18H21BrO3 365.27027 364 451

C19H23BrO3 379.29736 378

The compounds listed in the table were prepared analogously to the procedure of Example 262, starting from Example 344.

Molecular weight Ex. No. Structure Formula [g/mol] M + H 452

348.8735 349.1 453

306.7922 307.1 454

320.8193 321.1 455

334.8464 335.1

The compounds listed in the table were prepared analogously to the procedure of Example 262, starting from Example 329.

Molecular weight Ex. No. Structure Formula [g/mol] M + H 456

C19H24O3 300.401 301 457

C17H20O3 272.347 273 458

C18H22O3 286.374 287 459

C19H24O3 300.401 301

The compounds listed in the table were prepared analogously to the procedures of Example 260.

Starting material Yield Rf (Cyclohexane/ MS (CI) Ex. No. Structure Ex. No. [%] ethyl acetate 3:1) [M⁺+ 1] 460

104 0.16 394 461

104 0.29 394 462

104 0.13 424 463

104 0.24 424

EXAMPLE 464

At 0° C., a solution of 60 μl of 3 M sulphuric acid and 40 mg (0.23 mmol) of 2,3-dichlorobenzaldehyde in 400 μl of THF is slowly added to an open flask with 49 mg (0.2 mmol) of the compound from Example 104, dissolved in 1 ml of THF and 350 μl of methanol. After 5 minutes, 14 mg of sodium borohydride are added, at 0° C., to the solution, which is stirred well. The mixture is stirred at room temperature for another 10 minutes.

For work-up, the batch is diluted with 400 μl of water, made alkaline, with ice-cooling, using solid NaOH, and immediately extracted with MTB ether. The combined ether phases are washed with saturated sodium chloride solution, dried over magnesium sulphate, filtered and concentrated. Purification is carried out by column chromatography (mobile phase: cyclohexane:ethyl acetate 3:1).

Yield: 2.4 mg (3.0%)

R_(f): 0.40 (cyclohexane:ethyl acetate 3:1)

MS (EI): m/e=401 [M⁺]

Procedure Rf (Cyclo- MS Ex. Yield Starting analogous hexane:ethyl (EI: M⁺; No. Structure (%) Material to Example acetate 3:1) CI: M + H⁺) 465

40.7 104 464 0.52 313 (EI) 466

3.5 1A 1 0.19 299 (EI) 467

16 104 464 0.5  313 (EI) 468

8.1 1A 1 0.52 318 (EI) 469

3.1 1A 1 0.14 (1:1) 229 (EI) 470

35.6 1A 1 0.3 — 471

21.5 1A 1 0.31 353 (CI) [M + NH4+] 472

3.1 1A 1 0.21 352 (CI) 473

24.1 2A 1 0.38 309 (CI) 474

18.4 1A 1 0.31 351 (EI) 475

14.7 1A 1 0.4  402 (CI) 476

0.8 1A 1 0.43 —

The Examples listed in the table below were prepared analogously to the procedure of Example 127:

Molecular weight Ex. No. Structure Formula (g/mol) Mz + H 477

C22 H20 Cl N O3 381.8626 382 478

C22 H20 Cl N O3 381.8626 382 

What is claimed is:
 1. Compounds of the general formula (I)

in which A represents radicals of the formulae —CH₂—, —CO—, —CR⁴(OH)— or —(CH₂)_(a)—CHR⁵—,  in which a represents a number 0, 1, 2, 3 or 4, R⁴ represents hydrogen or (C₁-C₆)-alkyl and R⁵ represents phenyl, or  represents (C₂-C₈)-alkanediyl, (C₂-C₆)-alkenediyl or (C₂—C₆)— or (C₂—C₆)-alkinediyl, R¹ represents hydrogen, (C₃-C₆)-cycloalkyl or represents a 5- to 6-membered heterocycle which may contain up to 3 O atoms or a S atom or  represents a 5-to 6-membered benzo-fused heterocycle which may contain up to 2 O atoms or a S atom or  represents radicals of the formulae

 in which b and c are identical or different and represent a number 1 or 2, or  represents (C₆-C₁₀)-aryl,  where all of the ring systems listed above are optionally mono- to polysubstituted by identical or different substituents selected from the group consisting of halogen, cyano, nitro, trifluoromethyl, hydroxyl, (C₁-C₆)-alkoxy, (C₁-C₆)-alkyl-carbonyl and (C₃-C₆)-cycloalkyl, phenyl, phenoxy, benzyloxy and a 5- to 6-membered aromatic heterocycle having up to 3 O atoms or a S atom which for their part may be substituted up to three times by identical or different substituents from the group consisting of cyano and halogen,  and/or are substituted by (C₁-C₆)-alkyl and (C₂-C₆)-alkylene, which for their part may be substituted by halogen, (C₆-C₁o)-aryl or by radicals of the formula SR⁸,—OR⁹or —NR¹⁰R¹¹  in which R⁸ represents (C₁-C₆)-alkyl or phenyl, R⁹ represents hydrogen or (C₁-C₆)-alkyl, and R¹⁰and R¹¹ are identical or different and represent hydrogen, phenyl or (C₁-C₆)-alkyl, which is optionally substituted by phenyl, which for its part may be mono- to polysubstituted by identical or different substituents from the group consisting of halogen, nitro, hydroxyl and (C₁-C₆)-alkoxy,  and/or are substituted by groups of the formulae —CO₂—R¹³, —NR¹⁴R¹⁵, —NR¹⁶CO—R¹⁷, —NR¹⁸O₂—R¹⁹ and —CO—NR²⁰R²¹,  in which R¹³ represents hydrogen, or  represents (C₁-C₉)-alkyl or (C₂-C₆)-alkenyl, which for their part may be substituted by radicals of the formulae

 (C₆-C₁₀)-aryl or by a 5- to 7-membered aromatic heterocycle having up to 3 O atoms or a S atom  in which d represents a number 1 or 2, or  represents (C₆-C₁o)-aryl, which is optionally substituted by phenyl, which for its part may be substituted by cyano or halogen, R¹⁴ and R¹⁵ are identical or different and represent hydrogen, (C₃-C₆)-cycloalkyl, phenyl or (C₁-C₆)-alkyl, which is optionally substituted by (C₃-C₆)-cycloalkyl or phenyl, which for its part may be mono- to polysubstituted by identical or different substituents from the group consisting of halogen, hydroxyl or (C₁-C₆)-alkoxy, R¹⁶ represents hydrogen or (C₁-C₆)-alkyl, R¹⁷ represents hydrogen, adamantyl, (C₃-C₈)-cycloalkyl, (C₂-C₆)-alkenyl or (C₁-C₁₂)-alkyl which is optionally substituted by adamantyl, (C₃-C₆)-cycloalkyl, (C₆-C₁₀)-aryl, phenoxy or a 5- to 6-membered aromatic heterocycle having up to 4 O atoms or a S atom where aryl and the heterocycle for their part may be mono- to polysubstituted by identical or different substituents from the group consisting of (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy, hydroxyl, nitro or halogen,  and/or alkyl is optionally substituted by a radical of the formula

 in which e represents a number 0 or 1 and R²² represents (C₁-C₆)-alkyl or (C₁-C₁₀)-aryl, which is optionally mono- to polysubstituted by identical or different substituents from the group consisting of halogen, nitro, hydroxyl and (C₁-C₆)-alkoxy, or  represents (C₆-C₁₀)-aryl or a 5- to 6-membered aromatic heterocycle having up to, 3 O atoms or a S atom which for their part may optionally be mono- to polysubstituted by identical or different substituents from the group consisting of (C₁-C₆)-alkoxy, (C₁-C₆)-alkyl, hydroxyl, nitro and halogen, or  represents a radical of the formula

 in which L and M are identical or different and represent hydrogen or halogen, R²³ and R²⁴ have the meaning of R¹⁰ and R¹¹ given above and are identical to or different from this meaning, R¹⁸ has the meaning of R¹⁶ given above and is identical to or different from this meaning, R¹⁹ represents (C₃-C₈)-cycloalkyl, or represents (C₁-C₈)-alkyl or (C₂-C₈)-alkenyl, which for their part are optionally substituted by substituents selected from the group consisting of halogen, phenyl, hydroxyl, (C₃-C₈)-cycloalkyl and by a group of the formula —SiR²⁵ R²⁶ R²⁷,  in which R²⁵, R²⁶ and R²⁷ are identical or different and represent (C₁-C₆)-alkyl, R²⁰ and R²¹ are identical or different and represent hydrogen, adamantyl, (C₃-C₈)-cycloalkyl, phenyl, phenoxy-substituted phenyl or a 5- to 6-membered, aromatic heterocycle having up to 3 O atoms or a S atom  or  represent (C₂-C₈)-alkenyl, (C₁-C₁₂)-alkyl or (C₂-C₆)-alkinyl, which are optionally substituted by hydroxyl, (C₃-C₆)-cycloalkyl, (C₁-C₆)-alkoxy, halogen, hydroxyl, trifluoromethyl, phenyl or by a 5- to 6-membered aromatic heterocycle having up to 3 O atoms or a S atom where the ring systems are optionally substituted up to 2 times by identical or different substituents from the group consisting of (C₁-C₆)-alkoxy, (C₁-C₆)-alkoxycarbonyl, halogen, phenoxy, hydroxyl and (C₁-C₆)-alkyl,  and/or the alkyl listed under R²⁰/R²¹ is optionally substituted by radicals of the formulae —SCF₃.

 or —NR²⁸R²⁹,  in which R²⁸ and R²⁹ are identical or different and represent hydrogen or (C₁-C₆)-alkyl, R² and R³ are identical or different and represent hydrogen or (C₁-C₆)-alkyl, and D and E together form radicals of the formulae

 in which R³¹, R³², R³³, R³⁴, R³⁵, R³⁶, R³⁷ and R³⁸ are identical or different and represent hydrogen, phenyl or (C₁-C₆)-alkyl, and their pharmaceutically acceptable salts.
 2. Compounds of the formula (I) according to claim 1, in which A represents radicals of the formulae —CH₂—, —CO—, —CR⁴(OH)— or —(CH₂)_(a)—CHR⁵—,  in which a represents a number 0, 1, 2 or 3, R⁴ represents hydrogen or (C₁-C₄)-alkyl and R⁵ represents phenyl, or  represents (C₂-C₆)-alkanediyl, (C₂-C₄)-alkenediyl or (C₂-C₄)-alkinediyl, R¹ represents hydrogen, cyclopropyl, cyclopentyl or cyclohexyl, or represents benzofuranyl, benzothiophenyl, thienyl, or furyl, or  represents radicals of the formulae

 in which b and c are identical or different and represent a number 1 or 2, or  represents phenyl or naphthyl,  where all of the ring systems listed above 're optionally mono- to polysubstituted by identical or different substituents selected from the group consisting of fluorine, chlorine, bromine, iodine, cyano, nitro, trifluoromethyl, hydroxyl or (C₁-C₅)-alkoxy, (C₁-C₅)-alkylcarbonyloxy, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, phenoxy, thienyl, furyl or benzyloxy, which for their part may be substituted up to three times by identical or different substituents from the group consisting of cyano, fluorine, chlorine, bromine and iodine,  and/or are substituted by (C₁-C₅)-alkyl and (C₂-C₄)-alkenyl, which for their part may be substituted by fluorine, chlorine, bromine, iodine, phenyl, naphthyl or by radicals of the formula —SR⁸, —OR⁹ or —NR¹⁰R¹¹  in which R⁸ represents (C₁-C₄)-alkyl or phenyl, R⁹ represents hydrogen or (C₁-C₄)-alkyl, and R¹⁰ and R¹¹ are identical or different and represent hydrogen, phenyl or (C₁-C₄)-alkyl, which is optionally substituted by phenyl, which for its part may be mono- to polysubstituted by identical or different substituents from the group consisting of fluorine, chlorine, bromine, nitro, hydroxyl and (C₁-C₄)-alkoxy,  and/or are substituted by groups of the formulae —CO₂—R¹³, —NR¹⁴R¹⁵, —NR¹⁶ CO—R¹⁷ —NR¹⁸ CO₂—R¹⁹ and —CO—NR²⁰R²¹,  in which R¹³ represents hydrogen, or  represents (C₁-C₈)-alkyl or (C₂-C₅)-alkenyl, which for their part may be substituted by radicals of the formulae

 phenyl, naphthyl, thienyl or furyl,  in which d represents a number 1 or 2, or  represents phenyl or naphthyl, which are optionally substituted by phenyl, which for its part may be substituted by cyano, fluorine, chlorine or bromine, R¹⁴ and R¹⁵ are identical or different and represent hydrogen, cyclo-propyl, cyclopentyl, cyclohexyl, phenyl or (C₁-C₅)-alkyl, which is optionally substituted by cyclopropyl, cyclopentyl, cyclohexyl or phenyl, which for its part may be mono- to polysubstituted by identical or different substituents from the group consisting of fluorine, chlorine, bromine, hydroxyl or (C₁-C₄)-alkoxy, R¹⁶ represents hydrogen or (C₁-C₃)-alkyl, R¹⁷ represents hydrogen, adamantyl, cyclopropyl, cyclopentyl or cyclohexyl, or represents (C₂-C₄)-alkenyl or (C₁-C₁₀)-alkyl, which is optionally substituted by adamantyl, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, phenoxy-naphthyl, thienyl, or furyl, where the ring systems for their part may be mono- to polysubstituted by identical or different substituents from the group consisting of (C₁-C₄)-alkyl, (C₁-C₄)-alkoxy, hydroxyl, nitro, fluorine, chlorine and bromine,  and/or alkyl is optionally substituted by a radical of the formula

 in which e represents a number 0 or 1 and R²² represents (C₁-C₄)-alkyl, phenyl or naphthyl, which are optionally mono- to polysubstituted by identical or different substituents from the group consisting of fluorine, chlorine, bromine, nitro, hydroxyl and (C₁-C₄)-alkoxy, or  represents phenyl, naphthyl, thienyl, or furyl, which for their part may optionally be mono- to polysubstituted by identical or different substituents from the group consisting of (C₁-C₄-alkoxy, (C₁-C₄)-alkyl, hydroxyl, nitro, fluorine, chlorine and bromine, or  represents a radical of the formula

 in which L and M are identical or different and represent hydrogen, fluorine, chlorine or bromine, R₂₃ and R₂₄ have the meaning of R₁₀ and R₁₁ given above and are identical to or different from this meaning, R¹⁸ has the meaning of R¹⁶given above and is identical to or different from this meaning, R¹⁹ represents cyclopropyl, cyclopentyl or cyclohexyl, or represents (C₁-C₇)-alkyl or (C₂-C₆)-alkenyl, which for their part are optionally substituted by substituents selected from the group consisting of fluorine, chlorine, bromine, phenyl, hydroxyl, cyclopropyl, cyclopentyl, cyclohexyl and by a group of the formula —SiR²⁵R²⁶R²⁸,  in which R²⁵, R²⁶ and R²⁷ are identical or different and represent (C ₁-C₄)-alkyl, R²⁰ and R²¹ are identical or different and represent hydrogen, adamantyl, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, phenoxy-substituted phenyl, furyl, thienyl, or thiazolyl or  represent (C₂-C₆)-alkenyl, (C₁-C₁₀)-alkyl or (C₃-C₆)-alkinyl, which are optionally substituted by hydroxyl, cyclopropyl, cyclopentyl, cyclohexyl, (C₁-C₅)-alkoxy, (C₁-C₆)-alkoxycarbonyl, fluorine, chlorine, bromine, hydroxyl, trifluoromethyl, phenyl, furyl, or thienyl where the ring systems are optionally substituted up to 2 times by identical or different substituents from the group consisting of (C₁-C₄)-alkoxy, fluorine, chlorine, bromine, phenoxy, hydroxyl or (C₁-C₄)-alkyl,  and/or the alkyl listed under R²⁰/R²¹ is optionally substituted by radicals of the formulae —SCF_(3,)

 or —NR²⁸R²⁹,  in which R²⁸ and R²⁹ are identical or different and represent hydrogen or (C¹-C₄)-alkyl, or R² and R³ are identical or different and represent hydrogen or (C₁-C₃)-alkyl, and D and E together form radicals of the formulae

 in which R³¹, R³², R³³, R³⁴, R³⁵, R³⁶, R³⁷ and R³⁸ are identical or different and represent hydrogen, phenyl or (C₁-C₃)-alkyl, and their pharmaceutically acceptable salts.
 3. Compounds of the formula (I) according to claim 1 or 2, in which A represents radicals of the formulae —CH₂—, —CO—, —CR⁴(OH)— or (CH₂)_(a)—CHR⁵—,  in which a represents a number 0, 1, 2 or 3, R⁴ represents hydrogen or (C₁-C₃)-alkyl and and R⁵ represents phenyl, or  represents (C₂-C₄)-alkanediyl, propenediyl or (C₂-C₃)-alkinediyl, R¹ represents hydrogen, cyclopropyl or cyclohexyl, or represents benzofuranyl, benzothiophenyl, or thienyl, or  represents radicals of the formulae

 in which b and c are identical or different and represent a number 1 or 2, or represents phenyl or naphthyl,  where all of the ring systems listed above are optionally mono- to polysubstituted by identical or different substituents selected from the group consisting of fluorine, chlorine, bromine, iodine, cyano, nitro, trifluoromethyl or (C₁-C₄)-alkoxy, (C₁-C₄)-alkyl-carbonyloxy, cyclohexyl, phenyl, phenoxy or benzyloxy, which for their part may be substituted up to three times by identical or different substituents from the group consisting of cyano, fluorine, chlorine, bromine and iodine,  and/or are substituted by (C₁-C₄)-alkyl and (C₂-C₃)-alkenyl, which for their part may be substituted by chlorine, bromine, iodine or phenyl or by radicals of the formula —OR⁹ or —NR¹⁰R¹¹  in which R⁹ represents hydrogen or (C₁-C₃)-alkyl, and R¹⁰ and R¹¹ are identical or different and represent hydrogen, phenyl or (C₁-C₃)-alkyl, which is optionally substituted by phenyl, which for its part may be substituted by chlorine, bromine, hydroxyl or (C₁-C₃)-alkoxy,  and/or are substituted by groups of the formulae —CO₂—R¹³, —NR¹⁴R¹⁵, —NR¹⁶CO—R¹⁷, —NR¹⁸CO₂—R¹⁹ and —CO—NR²⁰R²¹,  in which R¹³ represents hydrogen, or represents (C₁-C₆)-alkyl or allyl, which for their part may be substituted by radicals of the formulae

 phenyl, or naphthyl, in which d represents a number 1 or 2, or  represents phenyl, which is optionally substituted by phenyl, which for its part may be substituted by cyano, chlorine or bromine, R¹⁴ and R¹⁵ are identical or different and represent hydrogen, cyclohexyl, phenyl or (C₁-C₄)-alkyl, which is optionally substituted by cyclopropyl, cyclohexyl or phenyl, which for its part may be mono- to polysubstituted by identical or different substituents from the group consisting of chlorine and (C₁-C₃) -alkoxy, R¹⁶ represents hydrogen, methyl or ethyl, R¹⁷ represents hydrogen, adamantyl, cyclopentyl or cyclohexyl, or represents (C₂-C₃)-alkenyl or (C₁-C₈)-alkyl, which is optionally substituted by adamantyl, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, phenoxy, thienyl or furyl, where the ring systems for their part may be mono- to polysubstituted by identical or different substituents from the group consisting of (C₁-C₃)-alkyl, (C₁-C₃)-alkoxy, hydroxyl, nitro, fluorine, chlorine and bromine,  and/or alkyl is optionally substituted by a radical of the formula

 in which e is a number 0 or 1 and R²² represents (C₁-C₃)-alkyl, phenyl or naphthyl, which are optionally mono- to polysubstituted by identical or different substituents from the group consisting of fluorine, chlorine, bromine, nitro, hydroxyl and (C₁-C₃)-alkoxy, or  represents phenyl, naphthyl, thienyl or furyl, which for their part may optionally he mono- to polysubstituted by identical or different substituents from the group consisting of (C₁-C₃)-alkoxy, (C₁-C₃)-alkyl, nitro, fluorine, chlorine and bromine, or  represents a radical of the formula

 or —NR²³R²⁴,  in which L and M are identical or different and represent hydrogen, fluorine or chlorine, R²³ and R²⁴ have the meaning of R¹⁰ and R¹¹ given above and are identical to or different from this meaning, R¹⁸ has the meaning of R¹⁶ given above and is identical to or different from this meaning, R¹⁹ represents (C₁-C₄)-alkyl or (C₃-C₅)-alkenyl, which for their part are optionally substituted by substituents selected from the group consisting of chlorine, phenyl, hydroxyl, cyclopropyl, cyclohexyl and by a group of the formula —SiR²⁵R²⁶ R²⁷,  in which R²⁵, R²⁶ and R²⁷ are identical and represent methyl, R²⁰ and R²¹ are identical or different and represent hydrogen, adamantyl, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, phenoxy-substituted phenyl, or thiazolyl or represent (C₂-C₃)-alkenyl, (C₁-C₇)-alkyl or (C₃-C₅)-alkinyl, which are optionally substituted by hydroxyl, cyclopropyl, cyclopentyl, cyclohexyl, (C₁-C₃)-alkoxy, hydroxyl, trifluoromethyl, phenyl, furyl, or thienyl, where the ring systems are optionally substituted up to 2 times by identical or different substituents from the group consisting of (C₁-C₃)-alkoxy, (C₁-C₆)-alkoxycarbonyl, fluorine, chlorine, bromine, phenoxy, hydroxyl and (C₁-C₃)-alkyl,  and/or the alkyl listed under R²⁰/R²¹ is optionally substituted by radicals of the formulae —SCF_(3,)

 or —NR²⁸R²⁹,  in which R²⁸ and R²⁹ are identical or different and represent hydrogen or (C₁-C₃)-alkyl, R² and R³ are identical or different and represent hydrogen or methyl, and D and E together form radicals of the formulae

 in which R³¹,R³²,R³³,R³⁴,R³⁵,R³⁶,R³⁷ and R³⁸ are identical or different and represent hydrogen or methyl, and their pharmaceutically acceptable salts.
 4. Compounds of the general formula (I) according to claim 1, in which A represents the —CH₂— group.
 5. Compounds of the formula (I) according to claim 4, in which A represents —CH₂—, R¹ represents phenyl or naphthyl,  where all of the above mentioned ring systems are optionally mono- to polysubstituted by identical or different substituents selected from the group consisting of fluorine, chlorine, bromine, iodine, cyano, nitro, trifluoromethyl or (C₁-C₄)-alkoxy,  and/or are substituted by (C₁-C₄)-alkyl,  and/or are substituted by groups of the formulae —NR¹⁶ CO—R¹⁷, —NR¹⁸ CO₂—R¹⁹ and —CO—NR²⁰R²¹,  in which R¹⁶ is hydrogen, R¹⁷ is (C₁-C₈)—alkyl, which is optionally substituted by cyclopropyl, cyclopentyl, cyclohexyl, phenyl, thienyl or furyl, where the ring systems for their part may ho mono- to polysubstituted by identical or different substituents from the group consisting of (C₁-C₃)-alkyl, (C₁-C₃)-alkoxy, hydroxyl, nitro, fluorine, chlorine and bromine, R¹⁸ has the meaning of R¹⁶ given above in claim 1, R¹⁹ represents (C₁-C₄)-alkyl or (C₃-C₅)-alkenyl, R²⁰ and R²¹ are identical or different and represent hydrogen, (C₂-C₃)-alkenyl, (C₁-C₇)-alkyl or (C₃-C₅)-alkinyl, which are optionally substituted by phenyl, furyl, or thienyl, where the ring systems are optionally substituted up to 2 times by identical or different substituents from the group consisting of (C₁-C₃)-alkoxy, fluorine, chlorine, bromine and (C₁-C₃)-alkyl, R² and R³ represent hydrogen or methyl, and D and E together form radicals of the formulae

 in which R³¹,R³²,R³³,R³⁴,R³⁵ represent hydrogen, and their pharmaceutically acceptable salts.
 6. Compounds according to claim 1, selected from the group consisting of:

where these compounds can be present as a racemate or as a pure enantiomer.
 7. Pharmaceutical composition, comprising as an active component at least one compound according to claim 1 mixed together with at least one pharmaceutically acceptable, essentially non-toxic vehicle or excipient.
 8. A method of treating cerebral ischaemias, craniocerebral trauma, states of pain or CNS-mediated spasms, comprising administering to a patient in need thereof an effective amount of a compound according to claim
 1. 